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Guy M. Benian, M.D. Pathology and Laboratory Medicine Muscle and cytoskeleton in C. elegans. The sarcomere performs the work of muscle contraction and is a "nano"-machine consisting of highly ordered assemblage of many proteins. Despite ever increasing knowledge of the components and functions of sarcomeric proteins (indeed new ones are discovered each year!), we still don't understand how scarcomeres are assembled, and maintained in the face of muscle contraction. Our lab is studying these questions in the model genetic organism, C. elegans. We have two main projects (1) the study of proteins (UNC-98, UNC-96, UNC-97) that are crucial for the connection between the transmembrane protein integrin and the myofibrils, and (2) the study of giant polypeptides (>700,000 Da) that have key roles in sarcomere assembly/organization and signaling (twitchin, UNC-89, TTN-1). The giant proteins consist primarily of multiple copies of immunoglobin (Ig) and fibroconectin type 3 (Fn3) domains, and one or even two protein kinase domains. One focus is determining the identity of proteins that interact with these giants that permits them to carry out their functions. Another focus is to learn the substrates of the protein kinase fomains, and to understand how the normally "autoinhibited" kinase domains become activated.

Jeremy M. Boss, Ph.D. Microbiology & Immunology Faculty Website: http://www.microbiology.emory.edu/boss/ Molecular immunology; regulation of major histocompatibility complex class II genes and tumor necrosis factor gene induction. Overlying simple gene regulatory mechanisms is the local chromatin architecture that controls the accessibility of a gene to specific transcription factors. Our lab investigates the role of chromatin in the regulation of genes in the immune system. In our model systems, we seek to elucidate the events that control major histocompatibility complex class II (MHC-II) genes and genes regulated by tumor necrosis factor. We employ animal, cellular, and molecular approaches in our studies. Key questions include understanding how transcription factors modify chromatin structure and how transcription factors interact over long distances to activate gene expression. Mice containing deleted regulatory elements are being created to develop in vivo model systems to interrogate gene assembly and chromatin modification questions. Through this type of analysis we hope to develop higher order models of gene regulation, through which specific factors may be targeted for immune based therapies used in infectious disease, autoimmunity, and vaccination.

Tamara Caspary, PhD Human Genetics Faculty Website: http://www.genetics.emory.edu/labs/caspary/caspary_lab_index.php Developmental Biology: Identification and functional analysis of previously uncharacterized genes important in mammalian development through forward genetic screens in the mouse. We ask directly which genes are important in mammalian development by performing unbiased screens in the mouse. We have identified several mutant lines with defects in neural development and in establishing a proper left-right body axis. Once we identify the novel proteins we combine molecular, cellular and genetic approaches to define the molecular mechanisms that cause cells to make specific cell fate decisions. For example, one current area of focus is a protein we identified called Arl13b whose loss results in abnormal cilia as well as abnormal motor neuron and oligodendrocyte cell specification. As all eukaryotic cells, including neurons, have a cilium we are interested in understanding the mechanistic link between cilia structure, cell signaling and proper specification of neurons. Through approaches including gene targeting, in vitro differentiation of embryonic stem cells, in vivo imaging of endogenous and tagged proteins and protein-protein interaction studies, we aim to better understand how cell signaling works to elaborate the mammalian body plan.

Anthony W.S. Chan, DVM Ph.D. Human Genetics Transgenic stem cell cloning and assisted reproductive technologies in disease modeling. My lab focuses on the development of genetically modified nonhuman primate model of human hereditary diseases such as Huntington's, Alzheimer's and Parkinson's etc. We are interest in developing transgenic monkeys that mimics patient genetic and pathologic alterations. These monkeys will be used for the understanding of disease development and the development of treatments. Additionally, somatic cell cloning, embryonic stem cell and reproductive technology are also developing in the lab, which is critical for the development cell replacement therapy. In order to achieve this goal, we investigate embryonic reprogramming in cloned embryo, epigenetic control in embryonic gene expression and differentiation process, viral and non-viral gene transfer, gamete and gonad cryopreservation and in vitro differentiation of embryonic stem cells.

Ping Chen, Ph.D. Cell Biology Planar cell polarity signaling in vertebrates Cellular polarization is a fundamental issue in developmental and cell biology. In particular, planar cell polarity (PCP) refers to coordinated polarization of cells within the plane of a cell sheet. PCP signaling is required for establishing epithelial PCP, such as uniformed orientation of sensory cells in the inner ear. In addition, PCP signaling drives a type of cell movement known as convergent extension (CE) that is essential for establishment of body axes and germ layers during gastrulation and for neural tube extension and closure. Our lab uses a combination of genetic model systems and in vitro cultures to dissect PCP signaling in vertebrates. Our favorite genetic model is the mouse auditory sensory organ. The mammalian auditory organ consists of precisely aligned sensory and nonsensory cells, providing a unique system for analyzing cellular patterning and polarity. In addition, we have started to explore the zebrafish system and examine multiple PCP-regulated cellular processes, such as gastrulation, neurulation, establishment of CPP in the lateral line and the inner ear.

Gordon George Churchward, Ph.D. Microbiology & Immunology Mechanisms of transposition. The study of whole genome sequences has revealed an extraordinary degree of lateral DNA transfer, not only between species, but between organisms as distantly related as bacteria and humans. In the bacterial world, lateral gene transfer has occurred frequently in the past, with bacterial species typically containing 3-10% "foreign" DNA. Conjugative transposons are found in Gram-positive bacteria, including many major human pathogens, and are important agents of genetic exchange in complex microbial communities. Some of these elements have an extraordinarily broad host range, and can move not only between different species and genera of bacteria, but also between bacteria and eukaryotes. We are interested in the biology of these elements. We are studying the recombination reactions that occur when these elements move, the mechanism of conjugation which permits the elements to move from one cell to another and the mechanisms that regulate these processes and their coordination. Our approaches are both genetic and biochemical. Our work has implications for the mechanism of lateral gene transfer and the spread of antibiotic resistance determinants between different bacterial species. We have recently begun a collaboration with the Scott lab to study the way by which a two component regulatory system called CovR/CovS functions to regulate the expression of approximately 15% of the genome of the human pathogen Streptococcus pyogenes. CovR acts primarily as a repressor of expressions of genes whose products are thought to play a major role in the pathogenesis of this organism which causes a variety of diseases ranging from self-limiting pharyngitis to necrotizing fasciitis (the so called flesh-eating bacteria). We are currently studying the biochemistry of the interactions between the regulatory protein CovR and the sites that it occupies in the promoter regions of the genes whose expression it regulates.

Anita H. Corbett, Ph.D. Biochemistry Faculty Website: http://www.biochem.emory.edu/labs/acorbe2/index.html Interplay between nucleocytoplasmic transport and cell-cycle progression in yeast. Nucleocytoplasmic transport is a critical element of virtually all signal transduction pathways. Classical signal transduction consists of a signal that originates outside the cell and is ultimately transduced into the nucleus often in the form of import of a transcription factor. Many common cellular responses to signals rely on the transcriptional upregulation of specific genes. The newly synthesized messenger RNA must then be exported from the nucleus to the cytoplasm. All macromolecules that cross the nuclear envelope move through large protein channels termed nuclear pores. Recent studies have found that in addition to the nuclear pores a number of soluble factors are required both for targeting substrates to the nuclear pore and for translocation across the pore. Our work focuses on understanding the detailed mechanisms of protein transport into and out of the nucleus and mRNA export from the nucleus.

Victor G. Corces, Ph.D. Biology Faculty Website: http://www.biology.emory.edu/research/Corces/ The goal of our research is to understand epigenetic mechanisms controlling the expression of eukaryotic genes. The main focus of our lab is to study the organization of the chromatin fiber within the eukaryotic nucleus and the mechanisms controlling this organization. Sequences involved in the establishment of this organization are called chromatin insulators. We have identified several different proteins that form a complex with insulator DNA and we are in the process of analyzing their function. The working hypothesis we are currently testing is that insulators are responsible for controlling patterns of nuclear organization required for cell differentiation. Alterations in insulator function that disrupt this organization could lead to cancer and other diseases. We are also interested in the role of the primary structure of the chromatin fiber, as determined by histone tail modification, in the regulation of transcription. In particular, we have found that phosphorylation of hitone H3 is an essential step during the promoter clearance process in the transcription of all Drosophila genes. The levels of phosphorylated histone H3 are maintained by a balance between the activities of the JIL-1 kinase and the PP2A protein phosphatase. We are currently exploring the mechanisms by which the activity of these two enzymes is regulated to control chromatin structure and transcription.

Gray F. Crouse, Ph.D. Biology Molecular genetics; DNA repair and recombination in yeast and mouse. Research in my lab centers on DNA repair in eukaryotic cells. We focus on the DNA mismatch repair system (MMR), which has been of great interest since the discovery of its central role in preventing colon cancer in humans. My lab was the first to clone a MMR gene in eukaryotes: the mouse Msh3 gene, but we now spend most of our time studying MMR in yeast because of the great number of genetic tools for yeast work and the relative ease with which we can do experiments that are impossible in bigger eukaryotes. We are studying the way in which MMR prevents mutations and blocks recombination between nonidentical sequences and the interplay between MMR, replication, and translesion synthesis.

Joseph Cubells, Ph.D. Human Genetics Research in this laboratory focuses on genetic contributions to human behavioral disorders including schizophrenia, major depression, PTSD, autism, and the 22q11 deletion syndrome. Part of the focus on such disorders is to understand in detail the genetics of relevant simpler traits ("endophenotypes"), including plasma activity of dopamine ?-hydroxylase and the human startle response. Another area of focus is candidate-gene analysis, with an emphasis on genotyping sufficient polymorphisms to account for most of the common variation at the locus. The following projects are currently funded: Linkage analysis of schizophrenia, conditional on plasma DBH activity and DBH genotypes. Longitudinal behavioral analysis of adolescents and young adults with 22q11DS. Analysis of glucocorticpid-receptor-related chaperone and co-chaperone gene expression in women with pregnancy-related major depression. Candidate gene analysis in civilian post-traumatic stress disorder.

Scott E. Devine, Ph.D. Biochemistry Faculty Website: http://devinelab.biochem.emory.edu Transposable genetic elements in model organisms and humans. Research in our laboratory is focused on transposable genetic elements in model organisms and humans. Transposable genetic elements, or "jumping genes" as Barbara McClintock called them, are discrete segments of DNA that can move from one site to another in the genomes of their hosts. We currently have two main projects in the lab. The first project is focused on discovering transposable elements that have been mobile in recent human history. Such elements represent a source of human variation, and, as endogenous mutagens, may also cause human diseases. The second project is focused on studying the retrovirus-like Ty1 element in yeast, with an emphasis on determining how Ty1 chooses integration sites in the yeast genome.

Paul W. Doetsch, Ph.D. Biochemistry Faculty Website: http://www.biochem.emory.edu/labs/medpwd Molecular biology of DNA damage and repair. Major areas of research focus in this laboratory are (1) the biochemistry, molecular biology and genetics of DNA repair in eukaryotes and (2) the interaction of the transcriptional machinery with DNA damage. Our DNA repair studies include the characterization of the repair of oxidative and ionizing radiation-induced DNA base damage in the nucleus and mitochondria as well as the elucidation of a broad specificity alternative excision repair pathway. Studies on the effects of various types of DNA damage on RNA polymerases have led to our current investigations on the generation of mutant proteins via transcriptional bypass and miscoding at sites of damage (transcriptional mutagenesis) and the concept that this type of event has important biological consequences, particularly in non-dividing cells. In addition, a more recent area of interest is the connection between different DNA repair and damage processing pathways and the relationship to genomic instability.

Jin-Tang Dong, Ph.D. Oncology/Hematology and Urology Molecular pathogenesis of human cancer - identifying genes mutated in cancer and dissecting their molecular pathways. The development and progression of cancer are driven by a series of mutations in a number of genes. The research in our laboratory involves both identifying novel cancer genes and studying how abnormalities of these genes cause cancer. For gene identification, we apply genetic and functional approaches to discover tumor suppressor genes located in chromosomal regions frequently deleted in human cancer. We have identified KLF5 from 13q21, FOXO1A from 13q14, ATBF1 from 16q22, and U50 from 6q15, but more genes remain to be discovered. We also identified WWP1 as an oncogene from 8q21, a chromosomal region often amplified in human cancer. The functions of these genes are being examined by tissue specific knockout or overexpression in mouse models and subsequent phenotypic and molecular analyses. Another important area of research is to dissect the molecular pathways involving these genes, especially KLF5 and ATBF1, by using biochemical approaches. We study how the signaling pathways are different between normal and cancer cells, and determine whether we can kill cancer cells by modulating the pathways. Such knowledge is useful for developing biomarkers in cancer detection and for therapeutic intervention in cancer treatment.

Michael P. Epstein, Ph.D. Human Genetics Statistical genetics and genetic epidemiology of complex human traits. I am primarily interested in the development of statistical methods for identifying genetic variants within humans that influence diseases and disease-related quantitative traits (e.g. blood pressure). My current research focuses on allele-based and haplotype-based statistical methods that identify genetic regions that are in linkage disequilibrium with disease. Additionally, I am involved in the development of flexible and powerful variance-component procedures for conducting linkage analyses of quantitative traits. My future research will explore the burgeoning area of high-dimensional genetic analyses. In particular, I am interested in the development of statistical methods for identifying large sets of genetic variants found throughout the human genome that collectively influence a quantitative trait of interest. In addition to developing such statistical methods, I am interested in applying them to real genetic studies of disease. Currently, I am involved in studies that seek to identify genetic variants that influence such disorders as PTSD, epilepsy, and diabetes.

Andrew P. Escayg, Ph.D Human Genetics Faculty Website: http://www.genetics.emory.edu/meet_our_team.php?faculty=escayg Understanding the molecular basis of common neurological disorders. Our lab uses a combination of human and mouse genetics, mouse disease models and genome analysis/bioinformatics in order to determine the molecular basis of inherited neurological disorders. We have a broad interest in neurological disease and the disorders that we are currently working on include epilepsy, ataxia and other movement disorders, and migraine. Of particular interest to us is the role of voltage-gated ion channels in disease. Voltage-gated ion channels play a critical role in neuronal signaling and the maintenance of normal nervous system function. Diseases that result from mutations in ion channel genes are called channelopathies. One component of our research involves the identification of families with inherited neurological disease. Once a suitable family is identified we begin the process of disease gene identification. To further understand disease mechanisms, we generate and study mice that carry the identified human mutations. We are also interested in understanding the genetic elements that regulate the expression levels of identified disease genes. This component of our research requires the use of bioinformatics, sequence analysis techniques, and cell culture.

Judith L. Fridovich-Keil, Ph.D. Human Genetics Roles of galactose and galactose metabolism in normal development, homeostasis, and disease. Galactose and its derivatives serve as essential components of glycoproteins and glycolipids in humans and other species. As a component of milk, galactose also serves as a key energy source for mammals, especially infants. Impaired metabolism of galactose leads to the potentially lethal disease classic galactosemia. We are applying a combination of basic and clinical approaches using patients, mammalian cells, flies, and microbial systems to explore the underlying bases of pathophysiology in galactosemia, and to define the roles of galactose and galactose metabolism in normal development and homeostasis. We are further working to develop novel and improved forms of intervention for patients with galactosemia

Andreas Fritz, Ph.D. Biology Molecular and genetic mechanisms of the early patterning of the nervous system and segmentation of the mesoderm. Research in my lab mainly centers on the early development of sensory organs. We use zebrafish as a model system to investigate the induction and formation of the otic and olfactory placodes, which give rise to the inner ear and nose, respectively. Development of sensory placodes has been a long-standing model to address general, important concepts of developmental biology, such as induction, inherent cellular properties, fate specification and maintenance. We use genetic and molecular approaches to identify and characterize genes important in these processes.

Peng Jin Human Genetics Faculty Website: http://www.genetics.emory.edu/labs/jin/jin_lab_index.php Noncoding RNAs and Epigenetic Modulation in Neural Development and Brain Disorders The importance of noncoding RNAs has been increasingly recognized within the last several years, particularly with the identification of new classes of small RNAs, such as microRNAs (miRNAs). These noncoding RNAs play important roles in neural development and can be involved in neuronal translation control (miRNAs) or transcription regulation (small modulatory RNAs in the fate specification of adult neural stem cells), and can be pathogenic (noncoding repeats in neurodegeneration). The ultimate goal of my lab is to understand the roles of noncoding RNAs in neural development and the pathogenesis of brain disorders. Currently we are focusing on several areas: 1) the role of microRNA pathways in learning and memory; 2) the molecular basis of RNA-mediated neurodegeneration; 3) small noncoding RNAs and epigenetic regulation; 4) chemical genomic approach to dissect small RNA pathway.

George H. Jones, Ph.D. Biology Mechanism and regulation of antibiotic synthesis in Streptomyces. We are interested in the biochemistry and evolution of RNA degradation pathways in bacteria and the relationship of RNA degradation to antibiotic biosynthesis in Streptomyces. We are particularly interested in (1) the regulation and function of polynucleotide phosphorylase in the synthesis of RNA 3'-tails in Streptomyces; (2) the role of the double strand specific endoribonuclease, RNase III, a product of the absB locus in Streptomyces coelicolor, in regulating antibiotic production; and, (3) the mechanisms of transcript processing in Streptomyces and the role of processing in the regulation of gene expression; and (4) the biochemistry and evolution of RNA polyadenylation in various bacterial species, particularly Bacillus. We utilize biochemical, genetic and bioinformatic approaches to study these systems.

William G. Kelly, Ph.D. Biology Molecular Analysis of Epigenetic Regulation in Germ Cells We use the genetic model system C. elegans to study how the "mother of all stem cells", the germ line, is established during embryogenesis and maintained during development. We have identified an "epigenetic erasure" process that separates pluripotent germ cells from somatic cells in the early embryo, and are studying epigenetic mechanisms in the embryonic germline that guard the germ cells during early development and regulate genomic activation. We also study how chromatin-based silencing mechanisms are targeted to large genomic regions, particularly the X chromosome, in adult germ cells. We have discovered imprinted X inactivation in C. elegans, and are using this as a model to analyze how genetic imprinting is established in gametogenesis. We have also recently identified mechanisms that silence unpaired DNA during meiosis, and are investigating how such mechanisms contribute to genome stability.

Steven W. L'Hernault, Ph.D. Biology Spermatozoa must create a unique cell surface to participate in fertilization My lab identifies and studies C. elegans mutants with defects in sperm surface assembly. C. elegans spermatozoa have secretory vesicles (MO) that fuse with and make the cell surface competent for fertilization. Many of our mutants affect MOs and we are determining how this organelle participates in cell surface assembly. Currently, we study several spe and fer genes required for MO function and/or cell surface assembly. The SPE-39 protein is required for MO biogenesis and it defines a new protein family required for vesicular trafficking, probably in all animals. The FER-1 protein facilitates MO fusion with the cell surface and its human homologs are implicated in muscular dystrophy and deafness. fer-14 and spe-42 are transmembrane proteins required for sperm-egg interaction during fertilization; the spe-42 gene has a mammalian homolog, of unknown function, expressed in testes. SPE-16 is an ubiquitin E3 ligase orthologous to Mind Bomb in vertebrates, where it negatively regulates Notch signaling. Mind Bomb is expressed during mouse spermatogenesis, but its role in this tissue is currently unknown. The spe-16 phenotype shows that Mind Bomb is required during spermatogenesis and we are currently determining its function.

Xiao-Jiang Li, Ph.D. Human Genetics Faculty Website: http://www.genetics.emory.edu/FACULTY/faculty_bio_xli.php Molecular mechanism of Huntington's disease and neuronal function of huntingtin associated proteins. Research in my lab focuses on the pathogenesis of inherited neurodegenerative disorders that are caused by an expansion of a polyglutamine tract in the associated disease proteins. These disorders include Huntington disease and several spinal cerebellar ataxia diseases. It is unclear how mutant proteins with an expanded polyglutamine tract cause late-onset and selective neurodegeneration despite their widespread expression in the body and brain. To elucidate how polyglutamine expansion causes neuronal dysfunction and degeneration, we are studying animal and cell models of Huntington and polyglutamine diseases using a variety of molecular genetic and neurobiological approaches including transgenic mice, primary neuronal culture, protein purification, and electron microscopy.

John C. Lucchesi, Ph.D. Biology Faculty Website: http://www.biology.emory.edu/research/Lucchesi/ Regulation of transcription; functional architecture of chromatin. The goal of our laboratory is to contribute to the understanding of gene transcription. In cells, DNA is wrapped around nucleosomes; this association must be altered in order for the factors and enzymes responsible for gene activation and RNA synthesis to access promoter regions and for transcription to proceed. As a model system, we have been studying the mechanism of function of a regulatory multi-protein complex responsible for enhancing the transcriptional activity of a large number of genes on the X chromosome of Drosophila males. Our experimental goals are to determine how the complex recognizes the X chromosome and how it interacts with X-chromosome chromatin to affect gene transcription. Recently, we have discovered the presence of a closely related complex in humans.

Hinh Ly, Ph.D. Pathology Faculty Website: http://pathology.emory.edu/AdminFacultyMember.cfm?Name_seq=1094 Telomere & Telomerase Dysfunctions in Human Diseases Telomeres are composed of repetitive DNA and proteins, located at the ends of linear chromosomes. We have recently identified numerous natural mutations in the telomere-synthesizing enzyme telomerase and in some of the telomere-associated proteins in patients who suffer from serious forms of blood disorders known as dyskeratosis congenita, aplastic anemia or leukemia. We are currently evaluating the functional consequences of these mutations in detail with the goal of understanding how they can lead to genomic instability, marrow cell death, and/or cancer development. Development of Novel Reverse Genetics Systems for Lassa Fever Virus: Lassa fever virus (LASV) can cause life-threatening hemorrhagic fever in humans and can potentially be employed as a bio-weapon. In order to work with this virus in a conventional BSL-2 laboratory, we have developed a simple and non-hazardous minigenome system for LASV, and other reverse genetics systems for the Pichinde virus that causes Lassa-fever like symptoms in guinea pigs. These plasmid-based systems have allowed us to test numerous questions about virus structure, replication, tropism, host immunological responses to viral infection, and disease pathogenesis in animal models. These efforts are aimed at developing novel and effective therapeutics and vaccines against virally induced hemorrhagic fevers in humans.

Ichiro Matsumura, Ph.D. Biochemistry Faculty Website: http://www.biochem.emory.edu/labs/imatsum/ Directed evolution of novel protein function; experimental determination of the adaptive mechanisms. I would like to learn how proteins evolve new functions. A better understanding of adaptive molecular evolution will teach us how the complex machinery of life arose, and enable us to improve the human condition by engineering new nanoscale devices. We recapitulate the evolutionary process in our lab by randomly mutating genes that encode proteins and expressing libraries of mutants in populations of micro-organisms. We screen these populations for mutant proteins that exhibit some novel function, and randomly mutate the isolated clones for the next round of screening. After many iterations of random mutation and screening, we can isolate, sequence and characterize the evolved proteins. This enables us to learn how beneficial mutations improve function.

Ken Moberg, Ph.D. Cell Biology Our lab uses the fruit fly Drosophila melanogaster to study how the developmental control of apoptosis and proliferation restricts tissue size in vivo. Work in the lab is currently focused on three novel growth-inhibitory genes: archipelago, erupted, and gang of four. archipelago and gang of four function cell autonomously to restrict tissue growth, while erupted functions non-cell autonomously. We have cloned archipelago and erupted, and the mapping of gang of four is underway. We have shown that archipelago inhibits growth by degrading protein targets that include Cyclin E and dMyc, the fly ortholog of the human c-Myc cancer oncogene. Analysis of the function and regulation of archipelago and erupted using both genetic and biochemical techniques are ongoing.

Charles P. Moran, Jr., Ph.D. Microbiology & Immunology Microbial genetics; gene expression during bacterial differentiation, RNA polymerase-promoter interactions. Research in my lab centers on the mechanisms that regulate gene expression and function during differentiation and development of bacterial endospores. These studies range from atomic level analyses of the mechanisms involved in promoter activation to microscopic studies of the assembly of subcellular structures.

Carlos S. Moreno, Ph.D. Pathology and Laboratory Medicine Faculty Website: http://morenolab.whitehead.emory.edu/ Bioinformatics and DNA microarray analysis of tumors. Research in my wet lab focuses on application of DNA microarrays to understand the molecular mechanisms of cancer progression, the changes in gene expression that are essential for tumor formation, and identification of new therapeutic targets. In our computational research, we are developing novel bioinformatics and systems biology tools to integrate microarray and genomic data in an effort to reconstruct mammalian transcriptional networks.

Andrew S. Neish, M.D. Pathology and Laboratory Medicine Molecular events in the process of inflammation. Dr. Neish's research focuses on the interactions of bacterial pathogens with human epithelial cells in an effort to understand the molecular mechanisms of pathological and symbiotic relationships. Bacteria are thought to mediate interactions with eukaryotic cells by translocation of preformed "effector" proteins. Currently, we are interested in a family of prokaryotic effector proteins that we have shown have profound effects on host cellular signaling functions. The effects clearly involve immune signaling, and may also influence cellular survival, proliferation and development. The laboratory employs a variety of microbiologic, genetic, biochemical and cell biological techniques to approach this question, including use of mammalian cell culture, murine and Drosophila models and large-scale expression profiling using microarray technology.

John M. Nickerson, Ph.D. Opthalmology Faculty Website: http://userwww.service.emory.edu/~litjn/ Retinal proteins and their expression in normal animals and in animal models exhibiting characteristics of human eye diseases. Whether as a treatment in human disease or as a laboratory tool, the delivery of nucleic acids into cells and expression of a gene is important. Many strategies have been proposed, and many to some degree, function as promised. Difficulties arise when migrating from a laboratory tool or proof-of-principle into a reasonable and effective therapeutic agent. Viruses and viral particles have been most effective so far, but they have drawbacks. Other approaches have not been as efficient. The invasiveness of current gene delivery schemes has been secondary to their efficiency and their associated risks such as immunogenicity. We are considering noninvasive technologies to circumvent many problems with present gene delivery approaches. We employ mouse models of human ocular genetic diseases in testing gene delivery.

David C. Pallas, Ph.D. Biochemistry Faculty Website: http://www.biochem.emory.edu/labs/dpallas/ Polyomavirus tumor antigen-associated proteins; regulation of cell-cycle control. The primary purpose of the research in my laboratory is to understand the molecular basis of the control of cell proliferation and of mechanisms by which this control is circumvented in neoplastic cell growth. Our major focus is PP2A, an important protein phosphatase that has been implicated in diseases such as cancer and Alzheimer's Disease. We are studying the cellular control of PP2A by both regulatory subunits and by covalent modifications such as methylation and phosphorylation. New insights will be applied to help identify new targets for small molecule drug therapy for diseases such as cancer and Alzheimer's Disease.

Jumin Peng, Ph.D. Human Genetics Pathogenesis of neurodegenerative disease Our focus is to study the pathogenesis of neurodegenerative disease using the state-of-the-art proteomics technologies based on mass spectrometry. These technologies enable us to identify and quantify hundreds to thousands of proteins and modifications (e.g. phosphorylation and ubiquitination) in a complex sample at sensitivity in the femtomole range. We are interested in profiling proteins and their modifications in patientÕs samples, which may lead to identification of proteins or modifications specially associated with the disease state when compared with normal individuals. The roles of these proteins and modifications in the pathogenesis will be further investigated. These studies may provide strategies for diagnosis and therapeutic intervention of these devastating diseases

Daniel Reines, Ph.D. Biochemistry Biochemistry and molecular genetics of RNA polymerase II transcription. The first of two projects examining the biochemistry and molecular genetics of RNA polymerase II transcription is a study of FMR1 transcription. We have characterized this transcriptionally silenced and heterochromatinized gene in terms of histone modification, DNA methylation, and loss of transcription factor binding. We are designing efforts to reactivate it using a variety of approaches. The second project is an analysis of transcription mechanisms using S. cerevisiae. Regulation of genes dependent upon elongation factors is being studied using genetics and biochemistry including genes involved in nucleotide metabolism. IMD2 transcription is induced with drugs that target this pathway and are used in patients as immunosuppressants. We can now observe inhibition of Imd2p in treated cells which should be therapeutically important.

Harold I. Saavedra, Ph.D. Radiation Oncology How loss of tumor suppressors and activation of oncogenes signaling through the CDK/RB/E2F pathway result in centrosome amplification, genomic instability and mammary tumors. Our working hypothesis is that oncogenes and loss of tumor suppressor activities initiate cancers by inducing centrosome amplification, aneuploidy and genomic instability. To test this hypothesis, we use a series of transgenic mice and various conventional and conditional knockout mice. The GFP-centrin-2 transgenic mice will be used as a marker to explore whether loss of p53 and E2F3, known suppressors of centrosome amplification, results in centrosome amplification in vivo, and whether inducible expression of Ras and Myc in mammary glands results in increases in centrosome amplification that precede mammary cancers. We will explore whether loss of tumor suppressors or activation of oncogenes induce centrosome amplification and tumorigenesis via the CDK/Rb/E2F pathway. The ultimate goal of our lab is to identify common targets that are unregulated by oncogenic and tumor suppressor pathways and that are critical to centrosome amplification and mammary tumorigenesis.

Subhabrata Sanyal, Ph.D. The primary goal of my laboratory is to study genetic determinants of learning and memory. We use Drosophila as a model system to investigate signaling networks that operate in neurons to modulate both pre - and post-synaptic plasticity. Enduring modifications in neuronal connectivity require synthesis of new proteins either through transciption. We have establish that conserverd signaling cascades such as those mediated by cAMP, PKA and MAPK operate in our model system to cause long-term change. These signaling cascades finally impinge on transcription factors to drive expression of "plasticity genes". Among several broad questions in the field that interest us are studying signaling cross-talk during plasticity and the identification and functional validation of target genes. Our overall aim is to ascertain how transcription factor networks are utilized in intact orgaisms, thus uncovering conserved [rinciples of learning across species.

Todd Schlenke, Ph.D. Biology Evolutionary genetics of immune response and toxin resistance in Drosophila. Our lab uses the fruitfly, Drosophila melanogaster, to study two traits that have wide ranging relevance for human health: the ability to fight off pathogens and the ability to break down environmental toxins. 1) Like many insects, Drosophila larvae are attacked by parasitoid wasps, which grow within and eventually consume the flies unless a successful immune response is mounted. We have identified several novel candidate proteins important for Drosophila's cellular immune response to parasites, and are pursuing the molecular biology and evolution of those proteins. We are also very interested in the evolutionary forces that maintain diverse infection strategies in competing wasp species, and the molecular basis for those differences. 2) Though Drosophila are not agricultural pests, they often come into contact with pesticides in nature and quickly evolve resistance. We identified a recent transposon insertion that causes overexpression of a detoxification gene and subsequent resistance to DDT. We are now conducting genome-wide screens for novel toxin resistance mutations in Drosophila using a wide array of insecticides and other environmental toxins, to understand how toxin-mediated selection pressures have reshaped genomes in the recent past.

Iain T. Shepherd, Ph.D. Biology Faculty Website: http://www.emory.edu/BIOLOGY/ishephe/ Molecular and genetic mechanisms in enteric nervous system development, using zebrafish. My lab studies the genetic basis of the development of the enteric nervous system (ENS) using the zebrafish model system. The ENS is the largest most complicated subdivision of the peripheral nervous system and is completely derived from neural crest stem cells (NCSC). The lab is interested in determining what genes are involved in the specification of the NCSC that form the ENS. We are also interested in determining what molecules are involved patterning the migration of NCSC in the intestine. We use genetic, cell biological and embryological experimental techniques in our studies. These studies are clinically important. Hirschsprung's disease is a pediatric ENS condition that affects 1 in 5000 live births the cause of which is only partly understood.

Stephanie L. Sherman, Ph.D. Human Genetics Genetic epidemiology of complex human disorders including chromosome nondisjunction and Fragile X Syndrome. Our research focuses on defining the variation in outcome of two syndromes and their related phenotypes: 1) Down syndrome (DS) and associated birth defects and 2) fragile X syndrome (FXS) and other gene related phenotypes (premature ovarian failure (POF) and tremor/ataxia syndrome (FXTAS)). For each, we use genetic epidemiological approaches ask specific questions identify genetic and environmental risk factors that increase susceptibility for each trait. Specifically for DS, we combine cytogenetic, molecular and epidemiological tools to examine the maternal age effect that increases the risk for chromosome nondisjunction. We also study genetic risk factors for DS-associated congenital heart defects. For FXS, we have a large study to understand the neuropsychological, neurological and reproductive profile of individuals who carry specific forms of the fragile X mutation.

James W. Thomas, Ph.D. Human Genetics Faculty Website: http://www.genetics.emory.edu/FACULTY/faculty_bio_thomas.php Comparative genetics of human disease and vertebrate genome evolution There is abundant phenotypic variation between species and within the human population. However, the genetic basis for most of this phenotypic variation is not known. The goal of our research is to use comparative genomics to address this fundamental gap in knowledge. In particular, our research uses a comparative genomics approach to identify when and how candidate functional genetic differences between species arose, and then to apply that knowledge to the development of better animal models of human disease and to a more complete understanding of the evolutionary history of the human genome. Ongoing projects in our laboratory include: the evaluation of a potential new mouse model of Lesch-Nyhan disease, targeted comparative mapping and sequencing in nonhuman primates, genomic characterization of a chromosome polymorphism in an avian model of social behavior, and analysis of near-identical but widely conserved segmental duplications on the X chromosome.

Erwin G. Van Meir, Ph.D. Neurosurgery, Hematology/Oncology and Winship Cancer Institute Faculty Website: http://neurosurgery.emory.edu/FacultyVanMeir.htm CNS tumor biology & genetics, HIF, angiogenesis, p53, oncolytic therapy, anti-cancer drug discovery Dr. Van Meir's research interests lie in understanding the molecular basis for human brain tumor development and how we can use this knowledge to devise new therapeutics that will improve patient survival. We examine how genetic alterations and hypoxia induce changes in cell biology that promote tumor formation with particular emphasis on tumor angiogenesis. We also develop novel therapeutic approaches for cancer using oncolytic adenoviruses and anti-angiogenic molecules including small molecule inhibitors of the hypoxia-inducible factor pathway.

Paula M. Vertino, Ph.D. Division of Radiation Oncology Š Winship Cancer Institute DNA methylation and epigenetic mechanisms of human carcinogenesis.

Stephen T. Warren, Ph.D. Human Genetics Faculty Website: http://www.genetics.emory.edu/labs/warren/warren_lab_index.php Human & medical genetics including the molecular basis of fragile X syndrome, autism and other psychiatric diseases. Our research is directed toward understanding the mechanisms of human diseases. A large component of the research program involves fragile X syndrome, a common cause of mental retardation and autism that is due to a trinucleotide repeat expansion in the FMR1 gene. The research is multifaceted and broad in approach. We work with patients as well as with model systems (mouse, fly, annnd cell culture) to understand the pathophysiology of the disorder. For example, biochemical and neurobiological studies are directed at understanding the consequence of the loss of FMR1 expression on local protein synthesis (the normal function of the encoded protein) in neuronal dendrites. Drosophila and mouse studies are aimed at discovering and evaluating potential drugs that may abrogate the loss of FMR1 function. Large-scale resequencing of FMR1 in patients is being undertaken to uncover conventional mutations and examine genotype/phenotype correlations. High-throughput diagnostics have been devloped for ongoing prevalence studies in 100,000 newborns. Other studies involve genome-wide analysis of copy number variation in humans as normal polymorphisms as well as pathological variants influencing schizophrenia or cognitive deficiencies.

Guang-Jer Wu, Ph.D. Microbiology & Immunology Molecular mechanism of METCAM/MUC18-mediated metastasis of cancer cells We are interested in studying the molecular mechanism of METCAM/MUC18-mediated metastasis of cancer cells of prostate, melanoma, breast, ovary, and nasopharyngeal carcinomas. METCAM/MUC18, a cell adhesion molecule in the immunoglobulin gene superfamily, promotes tumorigenesis and initiates metastasis of prostate cancer cells and increases metastasis of melanoma and ovarian cancer cells. On the contrary, METCAM/MUC18 may act like a tumor suppressor in some melanoma and breast cancer cell lines and perhaps nasopharyngeal carcinoma cells. We suggest that METCAM/MUC18 may have two opposite effects on the tumorigenesis and metastasis of cancer cells dependent upon different intrinsic factors in different cancer cell lines. Currently we are in the process of defining the functional domains and the ligands and regulators of human METCAM/MUC18 and studying transcription factors and signal transduction mediators that regulate their expression in normal versus cancer cells. We have recently found that a soluble protein derived from METCAM/MUC18 could block tumor angiogenesis and hence hematogenous spread of cancer cells in mouse models. We suggest that soluble proteins or peptides derived from METCAM/MUC18 may be a general blocker for the metastasis of all cancer cells.