Bio

My major scientific interest is the development of the approaches for representation and analysis of complex biological systems and how these approaches can be applied to the discovery of the molecular mechanisms contributing to complex heritable disorders. Our main emphasis is on neurodevelopmental and mental disorders (e.g. autism, schizophrenia, brain malformations), but recently we have started collaborations in cancer research as well.

Bio

Research in the Crispino lab is focused on investigating the regulatory mechanisms governing normal and malignant blood cell development, with an emphasis on understanding the growth of erythroid cells (red blood cells) and megakaryocytes (platelet-producing cells). In addition, we are greatly interested in learning how changes in normal essential regulatory molecules lead to human blood diseases, including leukemias, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs).

Research

My primary research interest revolves around modeling microbial ecosystem dyanmics using high-throughput sequencing data that describes the taxonomic and functional diversity of the system. Combined with physical, chemical and other biology variables measured in each ecosystem, I am working towards generating bioclimatic models of microbial ecosystems, that enable prediction of taxonomic and metabolic potential from remote sensing data (satellites and aircraft) across broad geographic and temporal space. Fundamentally I adhere to a system biology model, within which I aim to describe the community dynamics that yield the ecosystem services that humanity has come to rely on.

Bio

Previous Research: I was the Bioinformatics co-ordinator for the modENCODE project in the laboratory of Kevin P White. My work involved Identification of sequence-based functional elements and regulatory networks that control transcription in the fruit fly genome by integrating genomewide protein-DNA interaction profiles generated with tiling microarray and next-generation sequencing platforms (ChIP-chip or ChIP-seq), with other genomic datasets.

Current Research: I am a research fellow in Cheng Li’s laboratory at the Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute and the Harvard School of Public Health. My current research involves oncogenomics data integration with a special emphasis on Multiple Myeloma.

Bio

Anna Divoli was a postdoctoral scholar in Professor Andrey Rzhetsky’s lab from 2007 until 2011. She holds a Ph.D. in biomedical text mining from the University of Manchester (mentor: Professor Teresa Attwood) and carried out postdoctoral research in biomedical user search interfaces in the School of Information at the University of California, Berkeley (mentor: Professor Marti Hearst). Her research focuses on developing methodologies for acquiring biomedical knowledge from textual data and studying the effect of human factors in that process. Currently, she is a Senior Software Researcher for Pingar Ltd. For more information, please refer to Anna’s web site at http://www.ci.uchicago.edu/~divoli/

Bio

Jiang Liu identified SPOP as a biomarker in kidney cancer by using system biology approach. Now he is a professor in Beijing Institute of Genomics, Chinese Academy of Sciences.

Bio

Max was involved in using protein array and high-throughput fluorescent polarization (FP) in studying the comprehensive interaction profile of human SH2 domain proteins and ErbB families, androgen receptor (AR), as well as other receptor tyrosine kinase (RTK)s. Max was also involved in the development of high-throughput Western blot technology (Micro-Western Array, MWA). Max used the MWA and other functional assays to study the anticancer activity of natural compound caffeic acid phenethyl ester in prostate cancer cells.

Currently, Max has established his lab in NHRI. Research of Chuu lab focuses on studying the downstream signaling network of AR and liver X receptor (LXR) and their role in prostate and colon cancer using systems biology methods. 

Bio

I am interested in quantitatively studying the role of different metabolites in controlling oscillator dynamics in cyanobacteria.

Bio

Current research interests:
My research is centered around network growth models and topological metrics in complex networks.  We constantly reevaluate existing topological metrics in networks and strive to propose new measures which would help in a better understanding of complex networks. Realistic Network growth models which can explain empirical data is another major thrust area of research in our lab. 

Bio

As a student of Dr. Andrey Rzhetsky’s lab, she focused on data mining and data integration for drug target priotization;
Biomedical terminology/ontology evaluation

Now, Dr. Yao works as a scientist for GlaxoSmithKline, where she works on drug repurposing, biomarker discovery, patient stratification, combination therapy and other new business development by mining real world observatory data, in particular electronic health records (EHR) data.

Bio

My laboratory is engaged in a long term project to understand how DNA sequence specifies biological form. We are interested not only in the specification of typical form by a typical genome, but also in the effects of variability. Such variability might take the form of genetic variation in a population or intrinsic fluctuations in an individual. These problems touch on issues central to developmental and evolutionary biology, and efforts to solve them have previously led to the development of new branches of mathematics.
We consider these issues in the specific context of segment determination in the fruit fly Drosophila melanogaster, but actively seek collaborations with investigators working on other organisms or with pure theoreticians. The starting point for our own investigations are quantitative data on gene expression, extracted from images of confocally scanned fixed or living embryos. We use this numerical information to find parameter sets for specific models of fundamental processes of gene regulation and pattern formation by means of large scale optimization procedures performed on parallel computers. These models may be specified in terms of DNA sequence or be more coarse-grained. They might take the form of a dynamical system, deterministic or stochastic, or simply be a complex but explicit mathematical function.
Our goal is to use every tool in the toolbox—wet experiments, statistics, computational science, and mathematics—to solve a well focused scientific problem: how does a fly go from DNA sequence to a fate map of presumptive segments at single cell resolution? 

Bio

Ph.D. Department of Human Genetics- Dr. Di Rienzo’s group aims to characterize the amount and patterns of genetic variation in human populations, and to elucidate the forces that shape and maintain this variation. Forces such as demographic change or population structure exert genome-wide effects, while others, such as natural selection, result in locus-specific effects.

Bio

Amane assists with the daily operations of IGSB, including, but not limited to, coordinating the Institute’s monthly seminar series, handling the logistical details regarding events and meetings, and assisting the Director and the Grants and Project Managers with their grant proposals and other projects. Amane also makes sure that pertinent information continually circulates between the Institute and other departments within the University of Chicago.

Bio

I enjoy spending time with my family, flying airplanes, building experimental aircraft, photography, and computing.

Research

  Large scale compute and cloud administration, scalability, security,
  10Gbit networking, general network services, infrastructure build-out,
  equipment maintenance, supporting cloud computing users, and
  everything in-between.

Bio

I am a research technician for the ENCyclopedia Of DNA Elements (ENCODE) Project. The goal of the project is to identify all functional elements in the human genome through high-throughput sequencing. This project uses Bacterial Artificial Chromosomes (BAC) Recombineering to tag transcription factors with GFP in order to perform Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Once the BAC is transfected into K562 cells, I maintain the stable cell lines. After I extract the chromatin from the cells, I sonicate the chromatin then perform ChIP. Finally, the purified DNA generated from ChIP is sequenced using next generation sequencing.

Bio

Dr. Altman is a Professor of bioengineering, genetics, & medicine (and of computer science by courtesy) and chairman of the Bioengineering Department at Stanford University. His primary research interests are in the application of computing technology to basic molecular biological problems of relevance to medicine. He is currently developing techniques for collaborative scientific computation over the Internet, including novel user interfaces to biological data, particularly for pharmacogenomics. Other work focuses on the analysis of functional microenvironments within macromolecules and the application of algorithms for determining the structure, dynamics and function of biological macromolecules. Dr. Altman holds an M.D. from Stanford Medical School, a Ph.D. in medical information sciences from Stanford, and an A.B. from Harvard College. He has been the recipient of the U.S. Presidential Early Career Award for Scientists and Engineers, a National Science Foundation CAREER Award. He is a fellow of the American College of Physicians and the American College of Medical Informatics. He is a past-president and founding board member of the International Society for Computational Biology, an organizer of the annual Pacific Symposium on Biocomputing. He leads one of seven NIH-supported National Centers for Biomedical Computation, focusing on physics-based simulation of biological structures. He won the Stanford Medical School graduate teaching award in 2000.

Bio

Dr. Wold is the Bren Professor of molecular biology and Director of the Beckman Institute at Caltech. She began working on genome structure and gene regulation during embryo development for her Ph.D. thesis at Caltech, and developed ways to assay cis-regulatory element function during postdoctoral work at Columbia. She established joined the biology faculty at Caltech in 1981 where she and her colleagues have focused on learning the architecture and logic of gene networks that drive cell state transitions. They study skeletal muscle development, degeneration and regeneration as a favored model system. Recent work emphasizes new ways to quantitatively map the inputs and outputs of gene networks in a genome-wide manner using “next generation” ultra-high throughput DNA sequencing, and applying these methods to muscle and brain networks.

Bio

Dr. Schadt joined Rosetta as Informatics Analysis Research Leader in November 1999. He founded Rosetta’s Research Genetics department, whose primary mission is elucidating common human diseases using novel integrative genomics approaches based on genetic and molecular profiling data, and has helped define a new field in statistical genetics – the genetics of gene expression.  Prior to joining Rosetta, Dr. Schadt was a Senior Research Scientist at Roche Bioscience.  He received his B.A. in applied mathematics and computer science from California Polytechnic State University, his M.A. in pure mathematics from UCLA, and his Ph.D. in bio-mathematics from UCLA.

Bio

Dr. Young received his PhD from Yale University in 1975, and became a Whitehead Member in 1984. Scientific American recognized him as one of the top 50 leaders in science, technology and business in 2006 and his awards include a Burroughs Wellcome Scholarship, the Chiron Corporation Biotechnology Research Award, and Yale’s Wilbur Cross Medal.  Young has served as an advisor to Science magazine, the National Institutes of Health and the World Health Organization.

Research

Our laboratory is mapping the regulatory circuitry that controls cell state and differentiation in mice and humans.  We use experimental and computational technologies to determine how signaling pathways, transcription factors, chromatin regulators and small RNAs control gene expression programs in embryonic stem cells and differentiated cells.

Research

Conducts screens and maintains equipment in the Cellular Screening Center

Bio

Research Project: Currently, I am sequencing several endangered species and pests, including two bird sibling species (Kirtland Warbler and Cape May Warbler), the famous Lonesome George, whiteflies and the Chicago bed bug. Kirtland Warbler is endemic to only a few counties in Michigan and is listed as an endangered species by the International Union for Conservation of Nature (IUCN). Lonesome George is the last known individual of one subspecies of Galapagos Tortoise.
Whiteflies are the No.1 agricultural pests for most regions of the world. The bed bug is a noxious pest and has been drawing more attention recently due to its rapid expansion. The preliminary assemblies for the above species will be released soon.

Research

I’m studying transcriptional regulation in breast cancer cells, particularly how rare, non-synonymous single nucleotide variants influence protein function.
I’m a second year undergraduate student, currently working in Kevin White’s lab.

Research

I am a research technician for the modENCODE project in the White Lab. My job consists partially of fly husbandry and maintenance, including expanding and crossing lines, as well as screening for transformant flies (flies in which a given BAC construct has been successfully integrated into their genome). When I find transformants, I extract their DNA and use it to run polymerase chain reactions (PCRs), which serve to verify that the flies contain the correct constructs and tags. I also check the expression patterns of tagged proteins in these transformant lines by staining the embryos.

Research

Prostate cancer is the leading cancer diagnosis in American men, excluding skin cancer.  The natural history of prostate cancer is widely variable, and our insight into prognosis and response to therapy is guided mostly by pathology.  My project involves using sequencing data to evaluate prostate cancer progression, and to define prostate cancer subtypes.

Research

I got my phD in Biochemistry from the Johns Hopkins University School of Medicine.  My current projects include identifying co-occuring mutations in tumors and studying functional interactions between these mutations using Drosophila melanogaster as an in vivo model.

Bio

I previously worked with Douglas Nixon in Department of Experimental Medicine at University of California San Francisco as a research associate where I studied viral evolution.

Research

My research focuses on detecting signatures of positive selection on genomes of Drosophila melanogaster in response to experimental selection using next generation sequencing technologies. I am currently working with flies that have been exposed to severe hypoxia in the laboratory.

Research

The BAC Recombineering Core offers collaborative services to modify Bacterial Artificial Chromosomes (BACs).  One benefit that BACs provide is their size allows genes to be expressed at near endogenous levels by maintaining many surrounding regulatory elements.  However, their size also excludes them from being modified using conventional molecular techniques.  Using recombineering we are able to create mutations, deletions, as well as insert additional sequences such as GFP or antibiotic cassettes within BACs.  One of our ongoing projects is to GFP tag all the known Human Transcription Factors.  Our core director and I are happy to discuss how this service may benefit your research.

Bio

Dr. Dmitri Novikov is the Technical Director of the IGSB’s advances imaging core.  He is responsible for the Digital Scanned Laser Light Sheet Fluorescence Microscope (DSLM), acquired from the European Molecular Biology Laboratory.  This microscope takes advantage of a new optical arrangement using one objective for specimen illumination generating a thin optical sheet, and another objective for collecting the image data at various angles. This way, phototoxicity is reduced a hundred folds and more, and high resolution, fast live imaging of Drosophila embryonic development and other life processes becomes an exciting possibility

Research

Dr. Dmitri Novikov studying chromatin structure and function using polytene chromosomes of the fruit fly Drosophila melanogaster. The exceptional organization of the polytene chromosomes has made them a unique model system for visualization of genes. Indeed, only in these naturally “magnified” chromosomes can we distinguish sequences as short as several kilobase pairs as well as relate them to specific band and interband structures and study their transcriptional dynamics. A major barrier to full exploitation of polytene chromosome cytology has been the difficulty in producing good chromosome preparations. Dr. Novikov is using his new method applying high pressure and other modifications to overcome this barrier. Light microscopy images of such slides compared to electron microscopy images for the first time show similar or superior detail. 

Research

Recombineering Core Director Jennifer Moran is currently engaged in research to bring new Synthetic DNA technology into the repertoire of Core Facility technical services. Using commercially-available oligos as the raw material, we are able to synthesize virtually any DNA sequence we (or collaborators) can design in silico, up to about 1 kb. We have recently succeeded in joining three synthesized fragments (total length ~3 kb) and cloning them into an injectable integration vector (for Drosophila transgenics), using an efficient, one-step reaction. As this process is refined, it will open up numerous possibilities for creative projects. For instance, we are currently synthesizing a construct to permit RNAi knockdown of multiple genes in Drosophila. Our goal is to test the multiple knockdown of putative “cancer genes” in a combinatorial fashion in this model organism.
Dr. Moran and Recombineering Core scientist Alec Victorsen provide pre-experimental consultation to investigators who seek to incorporate advanced transgenic technology into their research programs.

Research

My laboratory combines optical microscopy of living cells and single molecules with biochemistry and mathematical modeling to understand the function of small networks of strongly interacting biological molecules.  These projects are motivated by the belief that explaining the origin of systems properties such as robustness to perturbations and adaptation to changing input will require understanding the nature of the molecular events that comprise the interactions.  To this end, we are interested in better understanding the intracellular environment in which biological systems function, including the role of subcellular localization, fluctuations in copy numbers of molecules, and changes in shared pools of metabolites.  We are actively developing optical and biochemical tools to study and control these effects in vivo and in vitro, including superresolution imaging based on localization of single molecules (STORM), which permits the study of protein organization within microbial cells.

We have recently been focused on a remarkable circadian clock found in photosynthetic cyanobacteria.  This may be the simplest of all circadian clocks, as the core oscillator can be reconstituted in a test tube using three purified proteins (KaiA, KaiB and KaiC).  The interactions between these proteins generate a stable ~24-hour oscillation in the level of phosphorylated KaiC.  We recently showed that phosphorylation occurs at two sites on KaiC and that the modification of these sites follows strong kinetic preferences.  This pattern of multisite phosphorylation coupled to protein-protein interaction is sufficient to drive stable oscillations.  We are studying the flow of timing information into the clock and the fidelity of information storage within the oscillator itself with the hope that the mechanisms employed here will have broad applicability throughout biology. 

Bio

Research:
(1) Working on the integrative analysis of regulatory elements for the modENCODE project Fly group.
(2) The cis-/trans- acting regulation in multiple species of fly and fly hybrids.

Bio

My research involves utilizing a combination of genomics, systems-biochemical, statistical, and computational approaches to study the role genetic variation plays in regulating transcription factor protein levels in the HapMap Yoruba population and growth factor-mediated signaling networks in breast cancer.

Bio

Dr. O’Brien joined the IGSB in February 2010.  She is interested in a range of belowground processes related to soil organic matter (SOM) cycling in a changing climate.  Her Ph.D. research was jointly advised by Miquel Gonzalez-Meler (University of Illinois at Chicago) and Julie Jastrow (Argonne National Laboratory), and focused on mechanistic controls on the rate and duration of SOM accumulation in restored perennial grasslands, especially the physical and chemical protection mechanisms that stabilize SOM.  Her postdoctoral research will expand on that theme by exploring the microbial processes that underpin the SOM dynamics observed over the landscape.  She will combine lab and field studies with next-generation molecular methods to link microbial community structure and function to SOM dynamics and the global carbon cycle.

Bio

Dr. Brulc joined IGSB in August 2009.  Her Ph.D. research was advised by Dr. Bryan A. White (University of Illinois Urbana-Champaign) and focused on the divergence of complex microbial communities and their resulting community interactions on host nutrition and diet adaptation in mammalian gastrointestinal tracts, as it relates to efficient fiber degradation, using second-generation DNA sequencing technologies.  Her postdoctoral work will expand on utilizing bioinformatics and newly developed genomics technologies to observe the microbial impact on human gastrointestinal disease states and also assessing metabolic potential differentiation and microbial influence on ecosystem development in topsoil environments.

Bio

Eric joined the Antonopoulos lab group as a research technician in July 2010. He uses a variety of molecular and microbiology techniques to prepare samples for next-generation DNA sequencing runs.
Eric earned his B.S. in Integrative Biology from The University of Illinois at Urbana-Champaign in May 2010. As an undergraduate, he gained research experience in Dr. Angela Kent’s lab where he studied microbial nitrogen transformations and used DNA “fingerprinting” approaches to examine changes in microbial assemblages in response to moisture gradients in restored wetlands. For the future, Eric plans on attending a graduate program where he can apply molecular biology techniques to address important issues in environmental engineering.

Bio

Bio

Dr. Aprison develops and oversees academic programs on campus through the auspices of the Chicago Center for Systems Biology (CCSB) and the Ph.D program in Genetics, Genomics and Systems Biology (GGSB).

Research

The IGSB Education & Outreach Director is Dr. Barry Aprison who develops and oversees academic programs on campus through the auspices of the Chicago Center for Systems Biology (CCSB) and the Ph.D program in Genetics, Genomics and Systems Biology (GGSB).

Bio

Dr. Roy Weiss is an expert in diseases of the thyroid and pituitary disorders—such as Cushing’s disease. Dr. Weiss has described several genetic diseases of the thyroid along with Dr. Samuel Refetoff. Together, they have one of the largest referral centers for genetic thyroid disease in the world. He also has one of the largest programs in the Midwest in the diagnosis and treatment of Cushing’s disease.

His research centers on the mechanisms of thyroid hormone action at the molecular, physiological, and psychological levels. Dr. Weiss has examined the molecular basis for the syndrome of resistance to thyroid hormone (RTH). He also has several clinical studies evaluating treatment of thyroid disease. Dr. Weiss’s research is supported by funds from the National Institutes of Health (NIH).

In addition to teaching medical student courses in physiology and pathology, Dr. Weiss currently holds a K24 award from the NIH to mentor fellows in clinical research.

He has been an invited speaker at national and international conferences. Dr. Weiss serves as associate editor of Thyroid and on the editorial board of the American Journal of Physiology. He has published more than 110 peer-reviewed articles on thyroid disease research and endocrinology.

Bio

An active researcher, Dr. Cunningham is studying the biology and therapy of hemoglobinopathies, the development of clinical trials for the treatment of genetic diseases, and transcriptional mechanisms operative during the development of vertebrate organisms. Over his distinguished career, Dr. Cunningham’s research has received support from the National Heart, Lung, and Blood Institute, the American Society of Hematology, and other prominent scientific organizations. He is vice chair of the American Cancer Society Molecular Genetics and Oncogenes Study Section.

Research

Mapping the regulatory wiring diagrams encoded in genomes is key to understanding development, disease and evolution. The White lab studies the coordinated action of networks of genes that control developmental and evolutionary processes. We have particular focus on building genome-wide models of transcriptional networks, and we use an integrated approach that makes use of gene expression microarrays, large-scale protein-protein and protein-DNA interaction analyses, systematic RNAi analysis and high throughput polymorphism detection. By applying our methods to both closely and distantly related species, we are investigating how conserved molecular networks control basic developmental processes and how variation in molecular networks translates into variation in organismal phenotypes. We are particularly interested in the transcriptional networks controlled by nuclear receptor proteins in development and disease. We also are studying the transcriptional mechanisms involved in patterning early embryos. We make use of the compact Drosophila genome and the genomes of related species as model systems for many of our studies, and recently we have also begun to apply these genomics and computational approaches to investigations of the human genome

Bio

The GS-FLX (454 Genome Sequencer) is run by Areej Ammar. Areej has a Bachelor of Science in Biochemistry from the University of Illinois at Chicago. Her previous lab experience was at the Department of Pharmacology, University of Illinois at Chicago where she worked on formyl peptide receptor signaling using various molecular biology techniques.

Bio

Microarray processing is performed by technician, Tifani Eshoo. Tifani earned her B.S. in Biochemistry at the University of Wisconsin-Madison where she worked in a plant genetics lab investigating the epigenetic mechanisms that control flowering time in A. thaliana under Dr. Rick Amasino. Before joining the IGSB she worked with Dr. Michael Axtell at Pennsylvania State University where she helped devise a novel experimental method referred to as degradome sequencing, utilizing the Solexa-Illumina sequencing platform. This was the first experimental method to sequence miRNA- mediated cleavage products on a high-throughput scale, providing empirical evidence for confirmation of computationally predicted miRNA targets as well as in vivo miRNA functionality in plant species.

Research

I am interested in transcriptional regulatory networks, and applications of next generation sequencing technology.

Research

I. Molecular genetics of species differentiation - The main interest is in the genetic and molecular basis of species differences. (You can think of human vs. chimpanzee, if you wish. How many genetic differences delineate us from them?) We use sibling species of Drosophila to get to the answers (see Wu, C.-I and C.-T. Ting 2004 Genes and speciation. Nature Review Genetics 5: 114-122). Among the traits of special interest are hybrid incompatibility and sexual behavior divergence. These traits are what define species.

Current approaches
In the past, we took a gene-by-gene approach and have successfully cloned two speciation genes (see the list below, or Wu and Ting 2004). In the beginning of this new century, there is a need and an opportunity to take a system-wide approach in order to identify the majority of genes involved in a particular process of speciation. We shall study the divergence in mating behaviors between the Z (for Zimbabwe) and M (cosmopolitan) behavioral races of Drosophila melanogaster (Wu et al. 1995; Hollocher et al. 1997a, b; Ting et al. 2001). These two races are at the very nascent stage of species formation.

We wish to understand the genetic and transcriptional bases of phenotypic divergence at this early stage of speciation. As shown in the figure above, the studies will be at 3 different levels - genotype, transcriptome and phenotype. The scope will be genomic and the tools will include genotyping tiling array, expression microarrays, large-scale sequencing, behavioral QTL mapping and, finally, precise gene replacement.

Aim 1 – At the genotypic level, we will identify nucleotide sites that are strongly differentiated between the Z and M races in a whole-genome scan of expressed genes. These race-differentiating sites will anchor genetic mapping of transcription and phenotypic divergence. We will construct multiply recombined (MR) lines between the Z- and M-races for such mapping.

Aim 2 – At the transcriptional level, we shall study the expression profiles of the MR lines (in heads and reproductive organs of the two sexes) and correlate these profiles with their underlying genotypes. The regulation of transcription is important in linking phenotype and genotype.

Aim 3 – At the phenotypic level, we shall first attempt to find the transcriptional basis of the phenotypic divergence (behavioral isolation), using the MR lines. We shall also link phenotypic divergence to genotypic changes directly. Genotyping will be done by whole-genome tiling array. We expect to identify most candidate “speciation genes” between the Z- and M- races and will carry out precise gene replacement (Rong and Golic 2000; Greenberg et al. 2003; Sun et al. 2004) to confirm their effects on the mating behavior.

II. Genomics and population genetics -The torrent of genomic data by DNA sequencing and expression microarrays have provided unprecedented opportunities for analyzing natural selection and adaptation. Speciation is the consequence of natural selection driving populations to adapt to different environments. It is also a genome-scale phenomenon.

Current approaches -We continue to carry out data analysis as done in the papers cited below. The data were often obtained from the public domain and we have been developing theoretical tools to analyze these data. At the same time, we also carry out large-scale data collection in collaboration with various sequencing centers in several countries. An example is our organization of an international consortium that sequenced 10,000 full-length transcripts from the macaque brain and testis (see Wang et al. in review). This effort will be the foundation of a comparative primate genome database. We also collaborate with these centers on many other fronts (see He et al. 2004 and Song et al. 2005 for the analysis of SARS evolution).

Research

Research

Dr. Solway’s laboratory addresses molecular mechanisms underlying airway constrictor hyperresponsiveness in asthma, including:
1) Regulation of smooth muscle gene expression (with focus on SRF and GATA5);
2) Evaluation of mutations and mechanisms underlying heritable cholinergic hyperresponsiveness in a kindred of ENU-mutagenized mice;
3) Functional genetics of asthma, (consequences of genetic variations and transcriptional analysis of endobronchial biopsies);
4) Molecular mechanisms that regulate the mechanical plasticity-elasticity (taffy-like vs. rubber band-like) balance in contracted airway smooth muscle.  

Research

My general interests include Bayesian and computational statistics, particularly when applied to problems in population genetics. Specific interests include:

* estimating haplotypes from population genotype data (for which I distribute a software package PHASE).
* developing statistical models for patterns of linkage disequilibrium across multiple loci, and using these patterns to identify recombination hotspots.
* spatial modelling of allele frequency variation.

Research

I am currently working on two projects. First, to complement the antibody production of the ModENCODE project, we are tagging Drosophila transcription factors with eGFP in ~20 kb BACs in the P[acman] vector. We are in the process of characterizing the expression patterns and functionality of these tagged constructs through anti-GFP staining of embryos and third-instar tissues and rescue experiments in lethal mutant backgrounds. We will follow this up with ChIP-Chip experiments with an anti-GFP antibody against the tagged protein to determine the DNA binding locations of these transcription factors. Ultimately, this procedure will be used to fill in any remaining gaps in the ModENCODE data set due to difficulty producing antibodies against certain transcription factors.

Second, I am looking at the genome wide transcriptional response to the juvenile hormone mimic methoprene in Drosophila cell culture and whole animals using microarrays.

Research

We focus on integrating technologies to sustainably produce biofuels and biobased products. The goal is to design fermentation and enzymatic conversion systems that will facilitate continuous product recovery. Currently we work on organic acids and alcohols. Recent work has
focused on:
* Anaerobic bacteria that utilize C1 compounds (H2, CO, and CO2)
* Enzyme and cell supported systems for biocatalyst stability and product separations
* Restricting nutrient requirements in fermentations

Other areas of interest are
* Metabolic engineering for novel biobased products
* Increased productivity in methanogenic communities

The team brings together unique capabilities from microbiology through chemical engineering to address these issues.

Research

Jonathan C. Silverstein, associate director of the Computation Institute of the University of Chicago and Argonne National Laboratory is associate professor of Surgery, Radiology, and The College, scientific director of the Chicago Biomedical Consortium, and president of the HealthGrid.US Alliance. He focuses on the integration of advanced computing and communication technologies into biomedicine, particularly applying Grid computing, and on the design, implementation, and evaluation of high-performance collaboration environments for anatomic education and surgery. He holds an M.D. from Washington University (St. Louis) and an M.S. from Harvard School of Public Health. He is a Fellow of the American College of Surgeons and a Fellow of the American College of Medical Informatics. Dr. Silverstein provides leadership in information technology initiatives intended to transform operations at the University of Chicago Medical Center and is informatics director for the University of Chicago’s Clinical and Translational Science Award (CTSA) program. He has served on various national advisory panels and currently serves on the Board of Scientific Counselors for the Lister Hill Center of the NIH National Library of Medicine.

Research

I seek to understand the mechanisms behind the evolutionary origin of new anatomical features and faunas. The philosophy that underlies all of my empirical work is derived from the conviction that progress in the study of evolutionary biology results from linking research across diverse temporal, phylogenetic, and structural scales. The Origin of Novel Faunas and Anatomical Systems: Much of today’s vertebrate diversity was defined by ecological and evolutionary shifts that happened during two critical intervals in the history of the Earth: the Devonian and the Triassic. These periods serve as the focal point for my research because they witness the origin of both new ecosystems and new anatomical designs. My expeditionary research supplies new fossils and a paleoenvironmental context to understand the origin of faunas, whereas our morphological, functional, and developmental studies yield hypotheses on anatomical transformations.

Over the past fifteen years, I have developed expeditionary research programs in Canada, Africa, the continental United States, Asia, and Greenland. These expeditions have led to new insights on the origin of major groups of vertebrates (mammals, frogs, crocodiles, tetrapods, and sarcopterygian fish). Future studies on the origins of pterosaurs, rhizodontid fish, dinosaurs, and salamanders will rely heavily on fossils discovered over the past five years. Examples include the newly discovered adult fin and juvenile skeleton of the fish, Sauripterus. These fossils are providing evidence on the ways that appendage function and skeletal development shifted during the evolutionary radiation of lobe-finned fish. Indeed, this evolutionary radiation is temporally linked to the origin of new freshwater environments. Consequently, the analysis of Sauripterus will place comparative studies of fin structure, development and function in a phylogenetic and paleoenvironmental context.

The goals of the paleontological research dovetail with those of my neontological studies. New fossils, such as Sauripterus, offer tests of hypotheses that derive from our comparative analysis of genetic and morphogenetic processes. For example, the comparison of developmental pathways common to the appendages of all animals suggests genetic mechanisms for parallel evolution and homology. Regularities of variation may reflect the fact that similar regulatory genes are used in the developmental patterning of diverse types of animals.

The Origin of Morphological Variation: The ~400 million year history of terrestrial animals reveals surprising patterns of anatomical stasis and parallel evolution: similar designs crop up in different species living in different environments. Salamanders, for example, arose over 150 million years ago, but have retained a very stable body plan in the face of environmental change and genetic variation. The study of these regularities transcends ecological and paleontological timescales because explanations of larger-scale patterns can be sought in the mechanisms that structure anatomical variation in populations today. Accordingly, my research has involved collecting data on intraspecific variation from diverse populations, developing predictive models of variation based on ontogeny, and comparing developmental processes in diverse salamanders that live in different environmental settings.

Salamander limbs are a model system to approach these issues because of the diversity of their developmental systems and life histories. In addition, the widespread occurrence of parallelism provides us with a window to develop predictive rules about the origin of variation in populations. Over the past seven years, colleagues and I have composed a database of limb variation and ontogeny in populations of diverse salamanders. Virtually all of the species analyzed to date possess variant conditions that both restore ancient features and anticipate more derived conditions seen in distantly-related species. Much of the observed intraspecific variation is predictable from a knowledge of phylogenetic history or development. Ultimately, if these historical and developmental effects resulted in long-term evolutionary patterns, they must have acted over geological timescales. Tests of this hypothesis will come from the study of the Chinese Cretaceous where, in collaboration with colleagues, I am studying variation of salamanders in a Cretaceous pond that were killed in a single mass-mortality event.

Phylogenetic analysis of ontogenetic trajectories in salamanders affords critical assessments of the role of historical, ecological, and structural factors in evolution. Analysis of development in salamanders with different life histories suggests certain aspects of early limb development are highly sensitive to variation in larval biology. I intend to explore this link between ontogenetic diversity and anatomical variation in the future by using experimental and comparative studies of ontogeny.

Research

Our laboratory examines the mechanisms and strategies whereby pathogenic bacteria cause human disease. Several different microbes are being investigated.

The cell wall of Staphylococcus aureus and other Gram-positive pathogens can be viewed as a surface organelle with anchored proteins that interact with the host environment during infection. Our research has revealed four different mechanisms of protein anchoring to the cell wall envelope. Surface proteins bearing a C-terminal sorting signal with a LPXTG motif are cleaved by the sortase A enzyme and linked to the cell wall crossbridges of peptidoglycan. This group of surface proteins is essential for pathogenesis and mediates bacterial attachment to host tissues and escape from the immune system. Surface proteins bearing a C-terminal sorting signal with a NPQTN motif are cleaved by sortase B. This mechanism is involved in iron transport during infection and is required for bacterial persistence in the host. Autolysins are enzymes that cleave the cell wall envelope at defined sites. One group of autolysins, e.g. lysostaphin and f11 hydrolase, is targeted to a receptor that is distributed uniformly over the bacterial surface. Another autolysins is targeted to the equatorial surface rings of staphylococci and mediates peptidoglycan cleavage at cell divisions sites. Our laboratory entertains genetic, molecular biological, biochemical, microscopic as well as animal infectious strategies to reveal mechanisms of protein targeting and the role in the establishment of disease. Our results are useful for the design of new therapies that can be used for the treatment of human infections caused by S. aureus and other Gram-positive bacteria.

Pathogenic Yersinia spp. invade their human hosts and colonize lymphoid tissues. This unique infectious strategy requires bacterial mechanisms of immune evasion. Yersinia type III secretion prevents the phagocytic killing of bacteria during infection. Further, the type III machinery intoxicates and kills immune cells, thereby impairing the host’s ability to clear invasive Yersinia. In fact, the pathogenesis of the most notorious of all pathogens, Yersinia pestis - the causative agent of plague, relies on the type III secretion machinery. We are interested in the mechanisms of protein recognition and transport by the type III machinery. Our results suggest that mRNAs of Yops, the substrates of the type III machinery, harbor signals that lead to the secretion of the encoded polypeptide chains. Current work is mapping the secretion signals and analyzing the mode of mRNA recognition by the type III machinery. A second area of research is the regulation of the type III secretion machinery. Upon bacterial entry into the host, Yersinia sense three environmental signals: a temperature shift to 37 ºC, glutamate ions as well as serum proteins. These signals trigger yersiniae to express and assemble the type III machinery and to transport YopB, YopD, YopR and LcrV into the extra-cellular milieu. Docking of yersiniae on the surface of immune cells leads to the insertion of type III secretion machinery needles into the plasma membrane of host cells and in sensing of the low calcium concentration of the cell’s interior. Yersinia respond to the low calcium signal by transporting YopE, YopH, YopM, YopN, YopO, YopP, YopT and YscM (LcrQ) into the cytosol of host cells. The sum of the function of these toxic proteins leads to a block in phagocytosis and in the killing of macrophages. Research on type III secretion represents a hotly contested frontier of microbiological science. Our results will be useful for the treatment of human infections caused by Yersinia, including the biological warfare agent Yersinia pestis, as well as several other Gram-negative pathogens.

Research

Daniel S. Schabacker received his PhD in Immunology / Protein Biochemistry at the University of Illinois, Urbana-Champaign. As Team Leader of the Biochip Group he is the lead scientist for the development of the Argonne National Laboratory biochip portfolio. In this role he is leading the development of nucleic acid and protein array applications. Working with both commercial licensees of the technology and governmental sponsors he coordinates product development of biochips and attendant hardware. Current research includes the development of, 1) a point-of-care human diagnostic respiratory biochip capable of rapidly identifying both bacterial and viral pathogens, 2) Veterinary diagnostic biochips capable of identifying causative organism(s) as well as antibiotic resistance for bovine respiratory syndrome and bovine mastitis, 3) Threat agent detection systems for rapid analysis (<15 minutes sample-to-answer) of multiple targets providing diagnostic confidence level outputs, and 4) Biochips and systems for biomarker discovery.

Research

The Proteomics and Informatics Services Facility provides investigators affiliated with CBC member institutions access to a number of mass spectrometers optimized for use in proteomics studies. The facility operates by syndicating the responsibility for the provision, operation and maintenance of these mass spectrometers to the RRC’s Mass Spectrometry Laboratory (MSL) and by syndicating sample preparation and fractionation activities to the RRC Protein Laboratory (PL). Scientists from these laboratories work together in conjunction with informatics specialists directly employed by the Proteomics facility to provide investigators with a range of services utilizing the combined capabilities of these laboratories.

Scientists employed and affiliated with the PSF can design and conduct experimental protocols, reduce and interpret data and provide pre-experimental consultation to investigators who seek to incorporate proteomic experimental strategies into their research programs. Researchers may submit samples to the facility for protein separation, post separation processing, mass spectroscopy and data analysis. Alternatively, qualified users may schedule instrument time to analyze their own samples. Two BioWorks workstations and one with Mascot and additional proteomics software may be scheduled for use. Please follow the links on the left for an online order page, scheduling various instruments, and a resource page to help you with protein purification.
The PSF also maintains close ties with investigators at UIC and other CBC member institutions (University of Chicago and Northwestern University) who specialize in Mass Spectrometry and Informatics research in order to provide opportunities for advanced collaboration, research referrals and protocol development.

The Proteomics and Informatics Services Facility was established by a grant from The Searle Funds at The Chicago Community Trust to the Chicago Biomedical Consortium.

Research

I am broadly interested in the evolution of development (Evo-Devo), evolutionary genomics and molecular evolution. The goal of the lab is to integrate developmental, genomic and computational approaches to understand the evolution of genes and gene functions. Currently we are pursuing two major projects:

1. The origin and diversification of the nervous system

The origin of multicellular animals was accompanied by an increase in the number of distinct cell types, chief among these being neurons. How and when did neurons arise in evolution? We are aiming to reconstruct the series of molecular events that led to their origin and subsequent diversification.

We are asking - What genes are expressed in all neurons, and no cells other than neurons? Such pan-neuronal genes comprise a molecular definition of basic neuronal features and thus provide a window into their origin. By using computational genomics we have discovered that many pan-neuronal genes in C. elegans share common motifs in their cis-regulatory elements, suggesting that their expression is controlled by a common set of transcription factors. We are currently combining experimentation with computational analyses of the C. elegans and other animal genomes to identify sets of genes that characterize different neuronal subtypes and will use these to elucidate the evolution of the animal nervous systems.

2. Evolution of transcriptional gene regulation

Although it is thought that morphological differences between species are largely caused by changes in regulatory DNA sequences, relatively little is known about their evolution. We are working to fill this gap by investigating the pattern and functional consequences of cis- and trans-regulatory evolution.

Research

Dr. Russell’s scientific training, background, experience, and productivity encompass a range of disciplines and forge linkages in the continuum between quantitative biology, bioengineering and physiology. Her current NIH support funds two collaborative projects, one on heart failure for regulation of protein synthesis and remodeling of cell shape, and the other on development of a novel cell culture system using bioengineering and surface chemistry modification. Many of her studies have been done in close collaboration with clinicians (muscular dystrophies, urinary incontinence, heart failure).

Research

Cancer is characterized by loss of normal cellular growth control. Intracellular signal transduction pathways are critical to the proper interpretation and integration of growth regulatory stimuli, and intricate mechanisms have evolved for ensuring the fidelity of cell replication. Small changes that alter the magnitude of these signals can significantly impact cellular outcomes. Thus, elucidating the nature of these signaling pathways and how they are modulated is central to understanding cell cycle control and the maintenance of genomic integrity. The focus of our laboratory is to determine the critical mechanisms that regulate cell growth and differentiation in response to growth factor or oncogenic stimulation and identify key targets for therapeutic intervention.

Research

My laboratory works at the interface between signal transduction and developmental biology. The long term goal of our research is to understand how complex developmental decisions are controlled in time and space by multiple signaling pathways. Our approach involves first identifying the individual genes comprising the regulatory network, and second elucidating the complex functional relationships between the components in order to determine the critical nodes where information is integrated. Specifically, we study how nuclear events downstream of the receptor tyrosine kinase (RTK) pathway regulate cell fate specification decisions during embryonic and retinal neural development, with particular emphasis on elucidating the post-translational control mechanisms that modulate and facilitate interactions within the network. Drosophila, and in particular the fly eye, provides an unparalleled model tissue in which to study the mechanisms of signal integration both because of its experimental tractability and because a complex interplay between multiple signaling pathways regulates many aspects of its development. Furthermore, because developmental signaling mechanisms have all been highly conserved in evolution, our work elucidating the molecular circuitries used in Drosophila directly advances understanding of how cell fates are designated and maintained in all animals, and why misregulation results in cancer and disease in humans. Thus our current and long term strategy involves combining genetic, genomic, proteomic, biochemical and cell biological methodologies in order to elucidate the conserved molecular circuitries that link and coordinate signaling modules in the developing retina.

Research

Our interest is in understanding how different evolutionary forces have shaped patterns of genetic variation in humans, and conversely, in learning about recombination, demography and selection from patterns of genetic variation observed in samples of extant humans. Our research combines modeling, the development of statistical tools and data analysis. The lab is “dry”, although we often collaborate closely with experimentalists.

Bio

Blum Riese Distinguished Service Professor of Medicine, Molecular Genetics & Cell Biology and Human Genetics. Dr. Janet Rowley is a pioneer in demonstrating that cancer is a genetic disease. Her work established that cancer is a genetic disease. She demonstrated that mutations in critical genes lead to specific forms of leukemia and lymphoma, and that one can determine the form of cancer present in a patient directly from the cancer’s genes. This changed the way cancer was understood, opened the door to development of drugs directed at the cancer-specific genetic abnormalities and created the paradigm that still drives cancer research.

Research

My laboratory is analyzing the genetic consequences of the recurring chromosome abnormalities seen in human leukemia cells. We have cloned several new genes at translocation breakpoints and are investigating how the chromosome rearrangements alter the structure of the genes and how this in turn alters the structure and function of the proteins. Many of the genes at these breakpoints are transcription factors, and thus the identification of the genes regulated by these proteins will be important. In addition, we are also mapping the region of chromsome deletions to identify the involved genes; these will most likely be tumor suppressor genes. These studies are carried out using not only molecular genetic techniques but also chromosome microdissection and fluorescence in situ hybridization of the appropriate probes to normal metaphase chromosomes and interphase cells as well as to cells from leukemia patients treated at the University of Chicago Medical Center.

Research

My research group tackles the following questions. What is the nature and extent of genetic variation within and between human populations? What are the biological and evolutionary processes that have produced the observed patterns of variation? How do genotypes contribute to phenotypes for complex traits (and how can we identify the relevant genetic variants)?

In our work, we develop new statistical methods for genetic analysis and also analyze data from humans and other organisms. Much of our statistical work makes use of computationally intensive approaches such as Markov chain Monte Carlo; these approaches can be effective for extracting subtle signals from large and complex data sets. In general, we aim to tackle problems where careful analysis, usually from a population genetic perspective, seems likely to yield new biological insights.

The scope of our past and ongoing research includes work in four main areas: (i) methods for gene mapping of complex traits; (ii) inference of population structure from genetic data; (iii) history and structure of human populations; and (iv) genome variation and evolution. We also distribute a number of programs and software packages, including the popular package structure for inferring population structure from genetic data [“Software” link above].

We are based in the Department of Human Genetics at the University of Chicago. Both our department, and the university in general, are very strong in population genetics, complex traits, and evolutionary biology. In particular we enjoy close ties with the labs led by Molly Przeworski, Matthew Stephens, Anna Di Rienzo, Nancy Cox and Carole Ober.

Research

I perform tissue culture and analysis of proteins, RNA and DNA for the Nuclear Receptor project. I am also responsible for lab safety.

Research

My lab studies the genetic basis of cancer susceptibility. Genetically, we are all very similar, but not identical. Some of this normal variation is insignificant, but some may have important functional consequences. Our goal is to discover the critical sources of functional heterogeneity in the pathways that are the barriers against the cellular transition from normal to cancer. We hope that these:

1. Will be clinically useful as biomakers of cancer risk by which cancer prevention
strategies can be indivualized based on each person’s unique genetic endowment.
2. Will point towards noveltargets for new rationally designed molecular
chemotherapeutics that short circuit abmormal pathways in cancer cells while
sparing cancer patients the toxicities of currently used treatments.
Cancer results from a mutation or a series of mutations that cause a cell to escape from normal regulatory controls. Cellular stresses such as DNA damage vastly increase the rate of mutation, and therefore, the likelihood of malignant transformation. Apoptosis, or programmed cell death, is the primary cellular defense against the oncogenic potential of these stresses, and so, our research has been focused upon understanding the genetics of apoptosis.

The p53 tumor suppressor is the central mediator of apoptosis. It is induced and activated by a variety of stresses, and thereupon initiates transcriptional response programs that result in apoptosis. Underscoring the importance of p53 is the observation that it is mutated in half of all cases of cancer. As would be predicted, concomitant defects in apoptosis are, in fact, a hallmark of cancer. If loss of p53 is so important for cancer, it is a paradox that p53 is almost never mutated in the most common pediatric cancer, acute lymphoblastic leukemia (ALL). This led us to hypothesize that even within the spectrum of normal, genetic variation results in heterogeneity in the p53-mediated apoptotic stress response. We found that susceptibility to DNA damage-induced apoptosis is a genetically determined program that is completely reproducible for a given individual, but which varies significantly among individuals. We have also identified several polymorphic variants within the p53 pathway that both alter the p53-mediated apoptotic response to stress, and which are associated with increased cancer risk.

We are now searching for other sources of genetic variation � both intrinsic to the p53 pathway and extrinsic to the p53 pathway—that alter susceptibility to damage-induced apoptosis, and which may be biomarkers for cancer susceptibility, or targets for new cancer therapies. Towards this end, we have four major projects ongoing utilizing both genome-wide and candidate gene approaches.

1. The identification of the genetic determinants of apoptosis:
Using about 400 cell lines from over 30 well-characterized multigenerational pedigrees, we are employing an unbiased genome-wide strategy to map by linkage analysis the genomic loci that contain the critical genetic determinants of DNA damage-induced apoptosis. As the polymorphic sequence variants identified by this study modulate the efficiency of the apoptotic response to oncogenic stress in different individuals, they are likely to translate into clinical tests by which cancer risk can be assessed and quantified.

2. The identification of the p53 network of apoptosis:
Although a number of p53 target genes have been identified, it remains unclear how p53 regulates apoptosis. We are using a genetic approach and expression microarray analysis to identify and model the p53-dependent transcriptional network of apoptosis. Identified p53 target genes will be attractive candidates for extensive resequencing to identify functional SNPs that may be clinically significant markers of disease risk. They may also be exciting novel targets for new therapeutics.

3. The identification of novel biomarkers and therapeutic targets in pediatric leukemia:
By array-based comparative genomic hybridization, we are mapping genomic regions amplified or deleted in pediatric ALL and comparing these to genomic loci commonly amplified or deleted in adult onset ALL. correlating this with a powerful predictor of outcome, the Day 7 bone marrow analysis. These regions will very likely contain oncogenes or tumor suppressors that are under selective pressure in ALL, and which may be biomarkers predictive of outcome, or novel therapeutic targets.

4. The identification of genomic susceptibility loci in secondary leukemia:
Using both genome-wide and candidate gene approaches, we are mapping susceptibility loci for secondary AML in a large and well-characterized cohort of patients. Because these patients develop leukemia following prior treatment with DNA-damaging agents, the identification of the genetic determinants of susceptibility may lead to insights into the critical genes and pathways by which cells generally respond to mutagens and other carcinogenic stresses, and thereby prevent oncogenesis. In addition, clinically, if cancer survivors at the greatest risk for the development of t-AML can be identified at the time of their initial diagnosis, then it may be possible to alter their chemotherapeutic regimen to reflect this risk, and thereby protect them from this devastating condition.

Research

tRNA is essential for protein synthesis and life. Genomes contain hundreds of tRNA genes. Translational regulation is related to the dynamic properties of tRNA that constantly change to facilitate stress response and cellular adaptation to new environments and to control gene expression in differentiated organisms. We developed microarray methods that measure tRNA abundance, its fraction of aminoacylation and misacylation at the genomic scale. We are exploring roles of tRNA in translational control in yeast and in mammalian cells including cancer. Over 100 types of post-transcriptional modifications have been identified in thousands of RNA sites from bacteria to man. They include methylation of bases and the ribose backbone, rotation and reduction of uridine, base deamination, elaborate addition of ring structures and carbohydrate moieties, and so on. RNA modification enzymes represent 1-2% of all genes in bacteria. Hundreds of guide RNAs and dozens of proteins are used to direct modifications in eukaryotic rRNAs. RNA modifications are involved in stress response, environmental adaptation, antibiotic resistance and human neurology. We developed genomic methods that detect and quantify changes in modification fraction. We are applying these high throughput methods to study the function of RNA modifications at the genomic level during cell growth, adaptation and development. Non-coding RNAs perform biological function without being translated into proteins. Some estimates suggest that in human, the number of non-coding RNAs may be comparable to the number of coding RNAs. We are working on methods for folding studies of non-coding RNAs, and for structural determination using cryo-Electron Microscopy. Folding during transcription is also studied to understand non-coding RNA folding in the cell..  

Research

The major research objectives of my laboratory are to identify genes that influence complex phenotypes, to understand their evolutionary history, and to elucidate how variation in these genes influences function. Our laboratory focuses on phenotypes related to fertility and to common diseases, and are conducted in a founder population, the Hutterites, and in outbred patient populations.

Our studies of fertility have focused primarily on HLA-region genes, including the non-classical HLA-G gene and the olfactory receptor genes in the extended class I region. These studies have indicated that genes in different HLA regions influence different components of fertility. For example, maternal-fetal compatibility for alleles at the class II locus, HLA-DRB1, is associated with reduced fecundity, maternal-fetal compatibility for alleles at the class I locus, HLA-B, is associated with sporadic fetal loss, while specific variants in the promoter and coding region of HLA-G are associated with both sporadic and recurrent pregnancy loss. We have recently completed a genome-wide screen for non-HLA loci that influence fecundity in the Hutterites and are initiating fine mapping and positionally cloning studies in selected regions.

Our studies of common diseases focus mainly on phenotypes that are associated with asthma and heart disease. In collaboration with Mary Sara McPeek and Mark Abney, we developed novel methods for quantitative trait locus (QTL) mapping in the Hutterites, and have studied >25 quantitative traits that are associated with common diseases. Fine mapping and positional cloning studies are underway for some of these traits. In addition, we have identified three chromosomal regions that house asthma-susceptibility loci (on 5p, 6p, and 19q) that are currently the focus of positional cloning studies in our laboratory in both the Hutterites and families ascertained as part of the Collaborative Study on the Genetics of Asthma (CSGA). Lastly, we collaborate with investigators at the University of Wisconsin – Madison on the Childhood Origins of ASThma (COAST) Study. This is a prospective cohort study of children at high risk for developing asthma and allergy, who are followed from birth onward. Our laboratory is genotyping the children in this study and their parents to identify genetic variation that influences the development of the immune system in the first year of life and the subsequent development of asthma and atopic disease, as well as variation that interacts with early life environmental exposures to influence these phenotypes. We have recently identified variation at several candidate loci with direct effects on first year immune and atopic phenotypes, and that interact with daycare exposure in the first year of life to influence the developing immune system.

Research

My research interests are diverse and include: treatment of breast cancer, especially in young or pregnant women; familial cancers; molecular genetics of cancer; cancer risk assessment and chemoprevention; breast cancer and minority populations and disparities in health outcomes. My clinical interests include breast cancer, cancer risk assessment, cancer prevention, and general hematology and medical oncology.

Research

Our group is interested in dissecting the architecture and function of gene regulatory networks. We investigate how the multiple transcription activators, repressors, boundary elements connected to a gene interact and orchestrate the precise tissue-specific and temporal-specific expression pattern of that gene. Understanding this process is critical since it is thought that malfunction of the regulatory program of certain genes underlie the cause of several human diseases. We focus on heart development and congenital heart diseases as substrates to test our hypotheses, and we use mouse and zebrafish genetic engineering, comparative genomics, bioinformatics and other high throughput genomic screening and validation strategies as experimental tools.  

Research

My main interest is in the area of evolution of gene regulation via genomic approaches.

Research

Signal Transduction

Reversible ubiquitination and regulation of signaling: Protein ubiquitination can have many outcomes depending on the length of the ubiquitin chain and the type of linkage. The 2004 Nobel Prize in Chemistry was awarded for the elucidation of the ubiutin-proteasome pathway in which proteins tagged with Lys-48-linked ubiquitin chains greater than 3 in length (polyubiquitination) are targeted to the proteasome for degradation. By contrast, short chains of Lys-63-linked ubiquitin act to coordinate the endocytic machinery and the internal trafficking of endocytic vesicles. We are interested ubiquitination as a regulated and reversible process that creates docking sites for a range of ubiquitin-binding proteins. We are currently studying the role of various ubiqutin linkages in regulating signaling events from activated cell surface receptors (the EGF-R and the T-cell receptor), and the role of specific deubiquitinating enzymes in modulating cellular signal transduction.

Systems Biology/Bioinformatics

The SH2-ome: The SH2 domain (http://sh2.uchicago.edu/) is a modular protein interaction domain that selectively binds to phosphorylated tyrosine containing sequences, and in doing so functions as the critical link between tyrosine kinases and downstream signaling. As such, SH2 domain containing proteins play key role in signaling cascades implicated in a wide range of human diseases, including cancers, diabetes, autoimmune diseases and a wide range of bacterial and viral pathogens. We have recently completed an initial bioinformatic analysis of the human and mouse complement of SH2 domains (Molecular Cell). In doing so, we identified a number of previously unknown SH2 domain proteins. We are utilizing a combination of chemical, biochemical, and cell biology techniques to determine the binding preference and cellular role of these novel proteins. We are also conducting an evolutionary analysis of SH2 domains using a variety of techniques, including analysis of intron-exon boundary structure, domains-assisted sequence comparison, structural and functional analysis.

Proteoscape: With support from the Cancer Center, we are developing a large protein-centered relational database to act as both an investigational tool as well as an underlying support database for future biomedical informatics. The modular nature of proteins involved in signal transduction and cancer (see our review published in Science 2003) is allowing us to develop detailed approaches to bioinformatic analysis of a wide range of proteins involved in health and disease. The SH2 domain website is the best developed resource based upon the Proteoscape database.

Self-Assembly and Complexity

Ultrasensitivity: We are interested in how binding interactions that depend on a high-local concentration of low-affinity binding sites can act to set thresholds, integrate signals and create all-or-none responses on a single cell level. We have previously identified the requirement for multi-site phosphorylation of the CDK inhibitor Sic1 to allow a productive interaction with Cdc4 - an event that controls the initiation of DNA replication and the G1 to S-phase transition in the cell cycle (published in Nature, 2001). A project is available to study a variety of aspects of this fundamental problem using computational modeling, biophysical and biochemical techniques.  

Research

What are the molecular pathways that dictate cardiac morphogenesis?  What is the ontogeny of Congenital Heart Disease (CHD), the number one birth defect world-wide?  How did the cardiovascular system evolve into a form that can support terrestrial life?  These intertwined questions are investigated in the Moskowitz laboratory.

Gene Discovery for CHD
We performed a gene discovery program using a forward genetic screen in mice to identify CHD-causing mutations (Kamp et al., 2010).  Our initial work was the first to link cilia signaling to heart development (Friedand-Little et al., 2011).  We have recently identified the CHD-causing mutations in several lines and are studying their effects on cardiac morphogenesis.

Cardiac Progenitor Specification and Cardiac Morphogenesis
Our recent work (Hoffmann et al., 2009) suggests that the molecular logic governing cardiac septation is firmly established within cardiac progenitors long before septum morphogenesis occurs.  In current studies we are identifying the genetic programs required in cardiac progenitors for septum morphogenesis.

Cardiac Conduction System
The Cardiac Conduction System (CCS) is a specialized network of cardiomyocytes responsible for coordinating the rhythmic contraction of the heart.  We have generated novel transgenic mouse lines for CCS-specific studies (Arnolds and Moskowitz, 2011).  These novel CCS-specific reagents are being used to investigate the molecular control of CCS development and adult CCS function.

Summary
Our laboratory studies basic questions in cardiac development and function.  We take biochemical, molecular, genetic, genomic and cellular approaches to these problems.  Our aims are to elucidate general principles of organ morphogenesis using the heart as a model, understand the ontogeny of Congenital Heart Disease, and contribute to our understanding of cardiac evolution. 
For more information, contact Ivan at .(JavaScript must be enabled to view this email address).

Publications
Friedland-Little JM, Hoffmann AD, Ocbina PJ, Peterson MA, Bosman JD, Chen Y,Cheng SY, Anderson KV, Moskowitz IP. A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet. 2011 Jun 8. [Epub ahead of print] PubMed PMID: 21653639.

Arnolds DE, Chu A, McNally EM, Nobrega MA, Moskowitz IP. The emerging genetic landscape underlying cardiac conduction system function. Birth Defects Res A Clin Mol Teratol. 2011 Jun;91(6):578-85. doi: 10.1002/bdra.20800. Epub 2011 Apr 28. PubMed PMID: 21538814.

Arnolds DE, Moskowitz IP. Inducible recombination in the cardiac conduction system of mink:CreERT(2) BAC transgenic mice. Genesis. 2011 Apr 18. doi: 10.1002/dvg.20759. [Epub ahead of print] PubMed PMID: 21504046.

Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE. Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected]. Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4006-11. Epub 2011 Feb 17. Erratum in: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5921.  PubMed PMID: 21330551; PubMed Central PMCID: PMC3053967.

Kamp A, Peterson MA, Svenson KL, Bjork BC, Hentges KE, Rajapaksha TW, Moran J, Justice MJ, Seidman JG, Seidman CE, Moskowitz IP, Beier DR. Genome-wide identification of mouse congenital heart disease loci. Hum Mol Genet. 2010 Aug 15;19(16):3105-13. Epub 2010 May 28. PubMed PMID: 20511334; PubMed Central PMCID: PMC2908466.

Hoffmann AD, Peterson MA, Friedland-Little JM, Anderson SA, Moskowitz IP. sonic hedgehog is required in pulmonary endoderm for atrial septation. Development. 2009 May;136(10):1761-70. Epub 2009 Apr 15. PubMed PMID: 19369393; PubMed Central PMCID: PMC2673765.

Moskowitz IP, Kim JB, Moore ML, Wolf CM, Peterson MA, Shendure J, Nobrega MA, Yokota Y, Berul C, Izumo S, Seidman JG, Seidman CE. A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell. 2007 Jun 29;129(7):1365-76. PubMed PMID: 17604724.

Research

Understanding the principles underlying CELLULAR QUALITY CONTROL — the integration of processes by which the cell senses, responds and adapts to environmental and physiological challenges — is among the most fascinating problems in biology. The appearance of incorrectly expressed or improperly folded proteins results in a cellular stress response involving activation of stress-induced transcription factors and leads to the elevated expression of molecular chaperones and proteases that serve to clear damaged proteins.

An imbalance in protein homeostasis results in the accumulation of misfolded and aggregation-prone proteins that are poorly refolded and degraded, often accumulating as oligomeric intermediate species and aggregates in different subcellular compartments. These events are hallmarks of human genetic diseases including the polyglutamine-expansion diseases such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, familial ALS, prion diseases, amyloidosis, cystic fibrosis, and a-1-antitrypsin disease. This has led to increased interest in the toxicity and pathogenesis of misfolded proteins and the role of protein aggregates in cellular dysgenesis.

Our laboratory is interested in the fundamental events that underlie the appearance of misfolded proteins and their consequence to protein homeostasis, cellular function, and organismal adaptation and survival.  

Research

A major obstacle to predicting plant responses to multiple environmental forcing factors is our lack of knowledge of the trade-offs between plant biomass allocation and nutrient acquisition. Thus, we believe that it will be necessary to factor in the attendant responses of mycorrhizal fungi to multiple-factor stressors. The ability of plants to adapt or respond to a changing environment is dependent on homeostatic capacities that minimize the cost of growth and biomass allocation. Plants’ responses to environmental stresses, such as nutrient limitation or anthropogenic effects suggest that they have a centralized system of stress response involving changes in nutrient and water use, carbon allocation, hormonal balances, and reliance on the mycorrhizal symbiosis.

Mycorrhizal fungi contribute to community processes and functions at various hierarchical organizational levels, through their establishment of linkages and feedbacks between whole-plants and nutrient cycles. Even though these fungal mediated feedbacks and linkages involve lower-organizational level processes (e.g., photo-assimilate partitioning, interfacial assimilate uptake and transport mechanisms; disease resistance), they influence higher-organizational scales that affect both community and ecosystem behavior. Hence, incorporating mycorrhizal fungi into research directed at understanding of the diverse environmental issues confronting society will require knowledge of how these fungi respond to or initiate changes in vegetation dynamics, soil fertility, or both.

My research addresses mechanisms controlling the growth and allocation of mycorrhizal fungi. Our premise is that predictions about whole-plant responses, especially those associated with multiple forcing factors, will require a better understanding of how mycorrhizal fungi respond to alterations in host allocation of assimilated carbohydrates and soil nutrients and how fungal responses feed back to the host.

Research

Dr. Meyer current work focuses on the analysis of shotgun metagenomics data sets and on the MG-RAST community portal for metagenomics. Shotgun metagenomics is benefitting directly from the current advances in sequencing technology, leading to dramatic growth in the number scientists using this approach and the number and size of the data sets being produced. He also has an interest in microbial genomics and the analysis of complete microbial genomes and is a member of the RAST project.

Bio

Megan McNerney received her training within the University of Chicago Pritzker School of Medicine NIH Medical Scientist Training Program. During her graduate work in Immunology she studied immune responses towards leukemia and bone marrow transplants, then completed residency training in Clinical Pathology at the University of Chicago with a focus on Clinical Molecular Diagnostics. She is currently a Leukemia & Lymphoma Society Fellow in Kevin White’s laboratory. Using next-generation sequencing, Megan is focused on characterizing the genome of therapy-related acute myeloproliferative neoplasms and other hematopoietic malignancies as a part of a larger effort by the IGSB to understand cancer pathogenesis.

Research

Alegre, ML and McNerney, ME. (2007) NK cell subsets in allograft rejection and tolerance. Current Opinion in Organ Transplantation. 12:10-16.

Lee, KM*, Forman, J*, McNerney, ME*, Stepp, S, Kuppireddi, S, Guzior, D, Latchman, YE, Sayegh, MH, Yagita, H, Park, CK, Oh, SB, Wulfing, C, Schatzle, J, Mathew, PA, Sharpe, AH, and Kumar, V. (2006) Requirement of homotypic NK cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions. Blood. 107:3181-3188. *Authors contributed equally.

McNerney, ME*, Lee, KM*, Zhou, P*, Molinero, L, Mashayekhi, M, Guzior, D, Sattar, H, Kuppireddi, S, Wang, CR, Kumar, V, and Alegre, ML. (2006) Role of natural killer cell subsets in cardiac allograft rejection. American Journal of Transplantation. 6:505-513. *Authors contributed equally.

McNerney, ME and Kumar, V. (2006) The CD2 family of NK cell receptors. Colonna, M and Vivier, E eds. Current Topics in Microbiology and Immunology. 298:91-120.

McNerney, ME, Guzior, D, and Kumar, V. (2005) 2B4 (CD244) – CD48 interactions provide a novel MHC class I-independent system for NK cell self-tolerance in mice. Blood. 106:1337-1340.

Kumar, V and McNerney, ME. (2005) A new self: MHC class I independent NK cell self-tolerance. Nature Reviews Immunology. 5:363-374.

McNerney, ME, Lee KM, and Kumar, V. (2005) 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells. Molecular Immunology. 42:489-494.

Vaidya SV, Stepp SE, McNerney ME, Lee JK, Bennett M, Lee KM, Stewart CL, Kumar V, Mathew PA. (2005) Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells. Journal of Immunology. 174:800-807.

Lee, KM*, McNerney, ME*, Stepp, SE, Mathew, PA, Schatzle, JD, Bennett, M, and Kumar, V. (2004) 2B4 acts as a non-MHC binding inhibitory receptor on mouse NK cells. Journal of Experimental Medicine. 199:1245-1254. *Authors contributed equally.

Yi, Y, McNerney, M, and Datta, SK. (2000) Regulatory defects in Cbl and Mitogen-Activated Protein Kinase (Extracellular Signal-Related Kinase) pathways cause persistent hyperexpression of CD40 Ligand in human lupus T cells. Journal of Immunology 165: 6627-6634.

Research

Toxoplasmosis causes loss of sight, hearing and brain damage in congenitally infected individuals. It also causes substantial morbidity and mortality in individuals immunocompromised by organ transplantation, malignancy or vasculitis and their therapy or AIDS.

Our laboratory has discovered Toxoplasma gondii specific secretory IgA (mouse and human) which can block T. gondii invasion of enterocytes, T. gondii specific cytolytic T cells, and demonstrated that a temperature sensitive mutant T gondii can confer protection against peroral and congenital T. gondii infection in a murine model. We have also demonstrated marked differences in genetic susceptibility to this infection and identified some of the responsible genetic loci. In separate experiments, we have discovered T. gondii antigen specific unresponsiveness in congenitally infected infants.

Our current experiments involve protective and harmful immune responses (in mice and humans) and constructing recombinant vectors for delivery of those epitopes that elicit protective immunity. Specifically, our research involves (1) defining T.Gondii epitopes recognized by protective CTL lymphocytes, (2) determining whether the critical protective immune function is cytolytic T cell function or gamma interferon production or both, and (3) incorporating the genes which encode proteins which contain epitopes that elicit protection into a DNA vaccine. This construct will be used to immunize human MHC transgenic mice (on a susceptible H-2b background) to determine whether it will protect against peroral and congenital infection.

We also are characterizing immunogenetics and pathogenesis and protection in this infection.

Research

The Matlin Laboratory studies the biogenesis of epithelial polarity in both cultured cells and epithelial injury models.

Research in the Matlin Laboratory is focused on understanding the biogenesis of apical-basal polarity in epithelial cells. Epithelial polarity is critical for the normal functioning of epithelial organs, such as the kidney and the gastrointestinal tract. Furthermore, the loss of epithelial polarity is an important contributor to the pathogenesis of disease following epithelial injury and carcinogenesis.

A primary current project is focused on deciphering how interaction of epithelial cells with the underlying extracellular matrix helps to orient the apical-basal axis in cells. In particular, we are examining how two forms of laminin, a major protein of the basal lamina, affect cell adhesion, migration, proliferation, and, ultimately polarization. One of these is laminin 332 (formerly known as laminin 5), a truncated form implicated in epithelial regeneration after injury. The other is laminin 511 (formerly known as laminin 10), a network-forming laminin whose assembly is believed to be required for polarization. Experiments in this area are conducted using Madin-Darby canine kidney (MDCK) cells, the leading mammalian model for the study of polarization mechanisms.

A variety of other projects are also underway or are being planned. These include examination of laminin involvement in regeneration of the renal tubular epithelium after acute or chronic kidney injury using mouse models, investigation of the roles of laminins in cancer metastasis, and determination of the effects of laminin 332 on network assembly of laminin 511 using atomic force microscopy. In addition, our laboratory is very interested in developing computational approaches to model epithelial polarization on a systems level.

Aside from work in the laboratory, we are also conducting research on the history and philosophy of cell biology, particulary in the modern period after 1970, and the relationship of the discipline of cell biology to the parallel discipline of molecular biology.

Research

The Lussier Research Group conducts research in the emerging field of phenomics, using computation to model phenotypes, integrate genomic with phenotypic datasets, and analyze phenomes in order to accurately individualize the understanding, the prediction, and the treatment of diseases.

- Modeling Phenotypes for comparative biology is our first focus. We design methods to automate the processes of integration, organization, visualization and datamining of non-molecular phenotypic data and knowledge.

- Comparative Phenomics, understanding phenotypic-genotypic interactions , is the second major focus of our research group.

- Integrating Biomedical Datasets across heterogeneous and semi-structured databases is our third complementary focus.  

Research

A fundamental problem in evolutionary biology is how genes with novel functions originate. My research focuses on this problem, although I am also interested in other issues of molecular evolution. Interest in evolutionary novelties can be traced back to the time of Darwin. However, studies of the origin and evolution of genes with new functions have only recently become possible and attracted increasing attention. Although conceptual revolution is always what we wish to pursue, the available molecular techniques and rapidly expanded genome data from many organisms mean that searching for and characterizing new genes is no longer a formidable technical obstacle. Molecular and evolutionary studies have provided powerful analytical tools for the detection of the processes and mechanisms that underlie the origin of new genes. Two levels of questions about this process can be defined. First, at the level of individual new genes, what are the initial molecular mechanisms that generate new gene structures? Once a new gene arises in an individual genome in a natural population, how does it spread throughout an entire species to become fixed? And, how does the young gene subsequently evolve? Second, at the level of the genome, how often do new genes originate? If new gene formation is not a rare event, are there any patterns that underlie the process? And, what evolutionary and genetic mechanisms govern any such patterns? I believe that an efficient approach to these questions is to examine young genes because their early processes of origination are directly observable. Pursuit of these problems requires an integrated approach incorporating molecular, genomic and population analyses. My lab applies such an approach to our studies. Using experimental and computational genomic analysis, we identified numerous new genes in Drosophila and mammalian genomes. Using molecular analysis, we revealed some important molecular evolutionary mechanisms responsible for their current gene structures. By evolutionary genetic analysis, we observed a significant role of the adaptive evolution in the determination of the fate of those new genes. Interesting patterns are observed associated with these new genes. I see questions there, challenges there, joys there…

Research

Transcription regulation in LNCaP cells and nucleocytoplasmic trafficking of steroid hormone receptors.