Faculty Profiles The MMG faculty are members of numerous departments within the Emory University School of Medicine, the School of Public Health, and Emory College as well as the U.S. Centers for Disease Control. Click on a faculty member's name to get more information about them and their research. · A · B · C · D · E · F · G · H · I · J · K · L · M · N · · O · P · Q · R · S · T · U · V · W · X · Y · Z ·

Rafi Ahmed, Ph.D. Professor of Microbiology and Immunology Director, Emory Vaccine Center ra@microbio.emory.edu Immunology and pathogenesis of chronic viral infections; immunological memory and vaccine development. Dr. Ahmed's research efforts are directed towards understanding the mechanisms of immunological memory and using this knowledge to develop novel immunological strategies and new and more effective vaccines. Current studies are focused on: 1. Understanding the differentiation and maintenance of memory CD8 T cells. 2. Comparing the quality of memory T cells induced by different vaccines. 3. Elucidating the nature of CD4 T cell help in maintaining CD8 T cell responses during acute and chronic viral infections. 4. Developing immunological strategies for enhancing T cell responses during chronic viral infections. 5. Understanding the mechanisms involved in generating long-lived plasma cells. 6. Analyzing immunological memory in transplant recipients.

Gordon George Churchward, Ph.D. Associate Professor of Microbiology and Immunology ggchure@microbio.emory.edu Mechanisms of transposition. Research activities are concerned with the maintenance and dissemination of genes encoding antibiotic resistance in bacteria. We are currently studying the mechanism of transposition of a group of genetic elements called conjugative transposons. These unusual elements, which generally confer antibiotic resistance on the host, are found in a wide variety of bacteria. Unlike other bacterial transposons, they are not only able to move from one place to another in the genome of an individual bacterium, but can transfer themselves from one bacterial host to another. The different hosts can belong to different species and genera. To understand how these elements can function in such a wide variety of hosts, we are studying how the process of conjugative transposition is regulated and how the process of conjugation works. Gene regulation in Group A Streptococci. 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.

Richard W. Compans, Ph.D. Professor of Microbiology and Immunology Director, Emory/UGA Influenza Pathogenesis and Immunology Research Center compans@microbio.emory.edu Role of viral glycoproteins in infection by enveloped RNA viruses; vaccine development. A major focus of our group is to develop virus-like particle (VLP) based vaccine antigens which are effective in eliciting protective immune responses against viral infection. One project is focused on vaccines for HIV-1 prevention, with specific emphasis on inducing broadly reactive neutralizing antibody responses to primary HIV-1 isolates to prevent infection at mucosal surfaces. A second project is to develop safe and effective vaccines to prevent pandemic influenza. We are also developing novel approaches for vaccine delivery, including direct application to the skin. In another project, we are investigating the functional activity of viral glycoproteins in mediating membrane fusion, which is involved in the entry of lipid-enveloped viruses into host cells. We are determining the critical amino acid residues which play a role in modulating membrane fusion and viral entry, and using structure-based drug design to develop small molecule inhibitors of viral fusion/entry.

Graeme Conn, Ph.D. Associate Professor of Biochemistry graeme.l.conn@emory.edu Our goal is to understand the molecular mechanisms of select biological processes of biomedical importance. Our current research aims to define: • The structure, substrate recognition mechanism(s) and function of ribosomal RNA modifying (methylating) enzymes that confer resistance to antibiotics. • The regulation of the ‘anti-viral’ protein kinase PKR by viral inhibitor non-coding RNAs and structured cellular activator RNAs. • The structure, ligand-selectivity and allosteric modulation of G protein-coupled receptors involved in mammalian chemoreception (e.g. taste

Cynthia A. Derdeyn, Ph.D. Assistant Professor of Pathology and Laboratory Medicine cynthia.derdeyn@emory.edu HIV/AIDS. My lab is interested in determining how HIV-1 (i) is transmitted heterosexually, (ii) escapes from neutralizing antibodies, and (iii) causes disease in an African cohort. Our studies are focused on analyzing samples collected from subjects enrolled in a large HIV-discordant couple cohort in Zambia (The Zambia-Emory HIV Research Project, Dr. Susan Allen, P.I.). We are interested in understanding the genetic bottleneck that occurs during heterosexual transmission in this setting, and also how the transmitted viruses evolve from a homogeneous population in their new host to a complex quasispecies of viral variants that escape neutralizing antibodies and eventually cause disease. Information provided from these studies will also be used to design Env-based vaccine immunogens targeted at eliciting a potent neutralizing antibody response.

Ruben Donis, Ph.D./D.V.M. Adjunct Professor of Pathology and Laboratory Medicine and Influenza Section, Centers for Disease Control and Prevention rdonis@emory.edu Molecular basis of influenza virulence and host switching; development of broadly protective influenza vaccines. Influenza is not an eradicable disease; the large pool of influenza in birds allows periodic emergence of pandemic viruses. Pandemics such as the 1918 Spanish influenza were major public health catastrophes. The major emphasis of our research is to understand the host range and pathogenicity of influenza in avian and mammalian hosts to design public health intervention strategies that mitigate the impact of pandemic and seasonal influenza. The fundamental premise or our work is that novel prevention or therapeutic interventions will require knowledge of the molecular mechanisms of disease and host protection. This is why we design studies to link the molecular structures and functions of virus and host to the mechanism of disease development. Our current research includes: (1) Studies on viral determinants of influenza host range and virulence. We use genetically engineered viruses to analyze the functions of the two major categories of viral proteins; 1a) hemagglutinin and neuraminidase surface proteins are being studied in glycan arrays, and receptor binding assays; 1b) viral replication complex proteins are currently studied by proteomics, microarray, and cell biology approaches. (2) Structural studies to understand how protein structure affects glycan binding specificity of the viral hemagglutinin and neuraminidase proteins. These studies are complemented by in vivo experiments to explain mechanisms of interspecies transmission and virulence. (3) Studies to understand the emergence of pandemic influenza by viral gene reassortment exploiting reverse genetics and organismal approaches. This research is revealing interesting novel functional properties of potentially pandemic strains. (4). Development of novel vaccines for epidemic and pandemic influenza. We analyze the structural basis of antigenic drift of the hemagglutinin to develop structure-based immunization approaches that expand the breath of the neutralizing antibody response to seasonal and pandemic influenza vaccines. Our studies are expected to discover novel approaches to assess the risk of interspecies transmission of influenza viruses and their severity as well as provide novel vaccines for prevention of influenza.

Linda Gooding, Ph.D. Professor of Microbiology and Immunology gooding@microbio.emroy.edu Mechanisms of adenovirus persistence in human lymphoid tissues and oncogenic potential of adenoviruses in lymphocytes. Work in the Gooding laboratory focuses on the interactions between infectious viruses and host immune defense mechanisms. Gooding and co-workers have described several countermeasures in human group C adenoviruses that protect the virus-infected cell from destruction by host cytokines of the TNF family as well as from lysis by anti-viral cytotoxic T cells. This group is also investigating the mechanisms of adenovirus persistence in human tonsil and adenoid tissues. Adenoviral DNA has been localized to T lymphocytes within mucosal lymphoid tissues, suggesting a possible latency mechanism. Current investigation focuses on identifying which T cell subsets harbor the virus and determining what signals lead to reactivation of viral replication in vitro. In addition, the group has established a model system in a human T lymphocyte cell line that mimics the behavior of the virus in tonsil T cells. This model will facilitate detailed analysis of the atypical virus life cycle that permits long-term association of the virus with T lymphocytes in vivo. One current hypothesis is that viral genes responsible for neutralizing host defense are uniquely regulated and act to protect the persistently infected T cell from destruction. Overall, it is anticipated that this work will contribute to a variety of different approaches to human disease from the development of viral vaccines, where genes that interfere with vaccine effectiveness will be identified and deleted from the immunizing strain, to the use of adenovirus as a vector for gene transfer, where viral genes that dampen host responsiveness will be expressed at high levels to prevent elimination of the transferred gene. In addition, the finding of adenovirus, with its known capacity for mutagenesis, in T cells that continue to divide provides strong incentive to reevaluate the real-life oncogenic potential of this DNA 'tumor' virus.

Arash Grakoui, Ph.D. Assistant Professor of Infectious Disease and Microbiology and Immunology arash.grakoui@emory.edu Hepatitis C virus (HCV) Hepatitis C virus (HCV) infection is a growing public health problem affecting 170 million people worldwide (~3 million in the United States). While twenty percent of patients infected with HCV are able to clear the infection after several months, the majority of patients become chronic carriers who, in addition to being the source for most new infections, can progress to chronic active hepatitis with cirrhosis and/or hepatocellular carcinoma (HCC). These clinical sequelae of HCV infection now comprise the leading indication for liver transplantation in the United States and account for 8-10,000 deaths each year in the United States alone. Despite its grave clinical consequences (i) no vaccine exists to prevent HCV infection and (ii) the only licensed therapy (alpha interferon (IFN_), either alone or in combination with the nucleoside analog ribavirin) for chronic HCV infection is expensive, associated with poor response rates, and laden with significant side effects. The paucity of efficacious anti-HCV therapeutic options highlights the need for effective interventions aimed at augmenting or supplementing the natural immune response and that alone or in concert with drug therapy can prevent the detrimental consequences of HCV infection. Development of such successful intervention strategies requires a thorough understanding of the host determinants of infection resolution. Our previous work has established the importance of the memory CD4+ T cell response in HCV infection resolution and prevention of viral escape as well as confirmed the importance of intrahepatic CD8+ T cells in viral elimination. Our laboratory is now focused on four main project areas utilizing murine, human and non-human primate experimental systems: To understand the role of regulatory T cell populations and NKT cells in facilitating HCV persistence and to define the functional and phenotypic differences between HCV-specific T effector cell populations in acute and chronic infection. To determine whether functional differences in HCV antigen presentation contribute to viral persistence. To define the impact of HIV co-infection on anti-HCV immune responses. To optimize antigen delivery systems utilizing antibody engineering as a vaccine strategy to optimally stimulate an anti-HCV immune response.

Eric Hunter, Ph.D. Professor of Pathology and Laboratory Medicine eric.hunter2@emory.edu Virus replication in vivo; determining T cell depletion and progression to AIDS. The research of Dr. Hunter's laboratory has centered on elucidating the virus-cell interactions involved in the assembly, entry and transmission of retroviruses. Understanding how the independently targeted capsid and glycoprotein molecules of the virus are transported to the assembly site(s), what cellular pathways are utilized, and what roles cell- and virus-encoded gene products play in this process, is a major focus of his research. Because the major viral components traverse distinct pathways, Dr. Hunter's laboratory has characterized the factors that influence intracellular transport and assembly of both viral capsids and the viral glycoproteins. He has also examined the signals and mechanisms that operate to include the viral glycoproteins into a budding virion and mediate fusion. More recently, this information on glycoprotein structure function has been applied to studies of the immunological and virologic correlates of HIV transmission in an African setting.

George H. Jones, Ph.D. Professor of Biology george.h.jones@emory.edu Mechanism and regulation of antibiotic synthesis in Streptomyces. Nearly 75% of all antibiotics used in clinical and veterinary medicine are produced by members of the bacterial genus, Streptomyces. These organisms make antibiotics as natural products during the normal course of their growth and development. While much information has been obtained in recent years relating to the mechanism and regulation of antibiotic biosynthesis, many important questions remain unanswered. Among these questions are: 1) what are the molecular signals that initiate antibiotic synthesis in producing organisms? 2) how are the various regulatory mechanisms that are known to affect antibiotic production coordinated by the cell? 3) how do organisms that are capable of producing more than one antibiotic coordinate those production pathways? 4) why do bacteria (and other organisms) produce antibiotics? 5) how did antibiotic production evolve? We are examining these and related questions in two model streptomycetes, Streptomyces antibioticus, an actinomycin producer and Streptomyces coelicolor which makes four different antibiotics. We are interested specifically in the following questions. 1) Do alternative RNA polymerase sigma factors play a role in the regulation of actinomycin production? We have cloned the gene for an alternative RNA polymerase sigma factor whose expression is required for the transcription of a gene or genes involved in actinomycin biosynthesis. The regulation of the expression of this gene and the coordination of its activity with that of other genes required for actinomycin production is under study in my laboratory. 2) Is there a relationship between RNA degradation and antibiotic synthesis in Streptomyces? The absB locus, encoding a homolog of ribonuclease III, globally regulates antibiotic production in Streptomyces coelicolor. We have characterized the absB gene product biochemically and plan to examine the molecular basis for that regulation using DNA microarrays. 3) Do the highly phosphorylated guanine nucleotides, ppGpp, and pppGpp regulate RNA degradation by inhibiting the activity of the enzyme, polynucleotide phosphorylase in Streptomyces? 4) Do E. coli, Streptomyces and Bacillus use different biochemical systems to polyadenylate RNA 3’-ends? If so, what can analysis of those systems tell us about the evolution of RNA polyadenylation in bacteria?

Daniel Kalman, Ph.D. Assistant Professor of Pathology and Laboratory Medicine dkalman@emory.edu Mechanisms by which enteropathogenic E. coli cause cytoskeletal & signaling changes in pathogenesis. The general goal of our laboratory is to understand how bacterial and viral pathogens interface with the host. We have focused on two mechanistic aspects of this interface: (i) the immunological detection and clearance of the infection, and (ii) host systems utilized by the pathogen to facilitate infection. Our work has focused on two pathogens: enteropathogenic E.coli (and the related enterohemmorhagic E. coli, the cause of "raw hamburger disease), and vaccinia virus (a relative of variola virus, the cause of smallpox). We have utilized a combination of experimental approaches including cell biology assays based on high resolution deconvolution microscopy, biochemical systems that permit reconstitution of cellular responses with cytoplasmic extracts in permeablized cells, mouse genetic systems that model human disease, and permit investigation of the immunological response to the pathogen, and a C. elegans model system which allows genetic dissection of both host and pathogen. A long-term goal of the laboratory is to develop approaches that will permit identification of agents useful in treating disease. There is considerable impetus for developing such agents to treat infections caused by bacterial and viral pathogens: development of resistance to antibiotic or other chemotherapies looms as perhaps the single most important public health concern confronting humans in the coming century. In this regard, our current efforts have led to the development and testing of novel inhibitors of pathogenic E.coli and poxvirus infections infections (e.g Reeves et al., Nature Medicine 11:731-739), which interfere with the interface between host and pathogen but not with microbial growth. As such, these inhibitors will not easily engender development of drug resistance. website: www.kalmanlab.net

Keith P. Klugman, M.D., Ph.D. Professor of Global Health, School of Public Health William H. Foege Professor of Professor of Medicine keith.klugman@emory.edu My research focuses on factors in the emergence of antibiotic resistant strains of pneumococci leading to predictions about the spread of resistance and the development of policies on immunization, along with research regarding acute respiratory infections, bacterial vaccines, and typhoid fever.

Bruce R. Levin, Ph.D. Professor of Biology blevin@emory.edu Population biology and evolution of bacteria; evolution and control of infectious disease. We do theoretical and empirical studies of the population biology and evolution of bacteria and their accessory genetic elements, and the population dynamics, evolution and control of infectious disease. Our theoretical work involves the development and analysis of the properties of mathematical and computer simulation models. Our empirical studies include experiments with laboratory populations (chemostat and serial transfer culture) of bacteria (primarily, but not exclusively E. coli) and their plasmids, phage and transposons. We also do studies of bacteria and their plasmids and phage isolated from natural populations. Currently, the students, postdocs and technician working with me, and I when I am lucky, (the “we� in this description) are engaged in four distinct projects: 1. the population genetics and molecular biology of the adaptation to the fitness costs associated with chromosomal resistance to antibiotics 2. the fitness costs associated with plasmid-encoded resistance and the nature and consequences of (co)evolution in modifying those costs 3. the within- and between-host population genetics/epidemiology of antibiotic resistance in hospitals.

Yuying Liang, Ph.D. Assistant Professor yliang5@emory.edu My lab is interested in studying the replication and pathogenesis of two classes of viral pathogens, influenza A virus and arenaviruses. Influenza virus causes annual epidemic infection and the occasional severe pandemics. We are interested in studying the virus-host interactions and the roles of host factors and signaling pathways in flu viral replication. Arenaviruses such as Lassa fever virus can cause hemorrhagic fevers in humans. A related non-pathogenic arenavirus Pichinde virus causes a disease in guinea pigs that mimics human Lassa fever. We are interested in studying the replication and pathogenesis of Pichinde virus in cell culture and in guinea pigs in order to shed lights on the molecular mechanism of the pathogenesis of human Lassa fever infection.

David Lynn, Ph.D. Howard Hughes Medical Institute Professor, Asa Griggs Candler Professor of Chemistry & Biology Professor and Chair of Chemistry david.lynn@emory.edu Dave Lynn’s group at Emory University works to understand the structures and forces that enable supramolecular self-assembly, how chemical information can be stored and translated into new molecular entities, and how the forces of evolution can be harnessed in new structures with new function. Such knowledge offers tremendous promise for discoveries in fields as diverse as drug design and genome engineering, pathogenesis and genome evolution, functional nanoscale materials and the origins of living systems. In the context of pathogenesis, Agrobacterium tumefaciens occupies a special place in the laboratory. This soil-borne alpha-proteobacterium has the capacity to transfer DNA from a resident tumor inducing (Ti) plasmid into eukaryotic cells where the oncogenic DNA (T-DNA) is integrated into the host genome and expressed. It is the only organism known to routinely engage in lateral gene transfer between Kingdoms, and the molecular basis of this transformation process has had considerable impact on studies of lateral DNA transfer and integration. In the case of Agrobacterium, virulent bacteria recognize signals produced at a host wound, phenols, monosaccharides, and low pH, as cues inducing expression of the Ti-encoded virulence (vir) genes. The vir gene products, among other functions, are necessary for the processing and transport of the T-DNA from the bacterium to the eukaryotic cell. We have employed biochemical and molecular genetic methods to develop a mechanism for the signal transduction process, revised models for signal perception, and are attempting to move the DNA transfer machinery to heterologous hosts.

Edward Mocarski, Ph.D. Professor of Microbiology and Immunology mocarski@microbio.emory.edu Dr. Edward Mocarski is currently the Robert W. Woodruff Professor of Microbiology and Immunology, and member of the Emory Vaccine Center. Dr. Mocarski studies the replication, latency and host response to herpesviruses, specializing in cytomegalovirus, an important opportunistic pathogen in immunocompromised hosts. Dr. Mocarski, together with the students and postdoctoral fellows he has helped train, has made significant discoveries into how cytomegaloviruses regulate gene expression, replicate their genomes, mature and spread during replication. He has explored the pathogen:host stand-off, investigating immunomodulatory viral functions as well as the properties of latency and reactivation that are central to viral pathogenesis. With collaborators, he has investigated chronic disease complications of cytomegalovirus infections. Dr. Mocarski's research has yielded targets for anti-viral therapies as well as information critical to vaccine initiatives.

Martin Moore, Ph.D. Assistant Professor of Pediatrics, Division of Infectious Diseases martin.moore@emory.edu Mucogenic Respiratory Syncytial Virus (RSV) Strains: Pathogenesis and Reverse Genetics RSV is the leading cause of bronchiolitis, viral pneumonia, and viral death in infants. RSV is the leading cause of respiratory failure and mechanical ventilation in infants. There is no RSV vaccine in use and no widely available therapies. RSV is not only a scourge of infancy but also a major cause of asthma exacerbations in children and adults, and a major cause of pneumonia in the elderly. Airway mucus is a hallmark feature of RSV lower respiratory tract infection. Mucus, necrotic epithelial cell debris, and inflammatory cells obstruct the airways, leading to characteristic wheezing and respiratory failure in severe cases. We identified and derived strains of RSV that exhibit differential disease phenotypes in mice. Some RSV strains induce high levels of the cytokine IL-13, airway mucus, severe histopathology, and pulmonary obstruction, whereas other strains induce a more protective TH1-type response. The primary focus of my laboratory is to define mechanisms of RSV immunopathogenesis and investigate the role of RSV strain differences in differential RSV pathophysiology. We are using differentially virulent RSV strains and a RSV reverse genetics system to dissect molecular mechanisms leading to airway mucus expression, bronchiolitis, and pulmonary obstruction in the mouse model. These studies may lead to much-needed effective vaccines and/or therapies for RSV disease. A comprehensive understanding of how RSV strain differences affect pathogenesis and immunity will require bridging gaps between basic research, epidemiology, and clinical studies.

Charles P. Moran, Ph.D. Professor of Microbiology and Immunology moran@microbio.emory.edu Microbial genetics; gene expression during bacterial differentiation, RNA polymerase-promoter interactions. The work in our laboratory focuses on the control of gene expression during bacterial differentiation. Asa the bacterium Bacillus subtilis differentiates from the vegetative form into a dormant endospore, complex morphological and physiological changes occur that require the expression of many genes. During the process, new RNA polymerase sigma subunits appear (oF, oE, oG, oK), displacing one another and conferring on the RNA polymerase different specificities for the recognition of different classes of promoters. One focus of our laboratory is to elucidate the mechanisms that regulate sigma factor function. For example, the DNA binding protein SpoOA responds to environmental signals by activating the transcription of several key operons at the onset of sporulation. We are currently testing the model in which SpoOA, when bound to promoter DNA, interacts directly with the RNA polymerase sigma subunit. We are also studying an example of regulation of gene expression by a morphological cue. During sporulation B. subtilis divides into two compartments (forespore and mother cell) that follow different developmental paths. Forespore-specific transcription is initiated by oF-RNA polymerase, and results in the forespore-specific production of oG, which directs the subsequent forespore-specific transcription. However, oG does not become fully active until engulfment of the forespore is completed. We want to know how the activity of oG is coupled to this morphological change. We have shown that the anti-sigma factor SpoIIAB may play an important role, and now we are attempting to identify additional genes whose products regulate oG activity. The utilization of gene products during the assembly of the complex morphological structures of the spore is governed both by the order of their synthesis, and by the order of their assembly into these structures. It is not known how these two mechanisms are coordinated. Transcription of several genes encoding spore coat proteins is directed by oK, the last o of the cascade. However, premature synthesis of spore coat proteins does not result in the premature assembly of spore coat-like structures. We are attempting to elucidate the mechanisms that regulate the utilization of spore coat proteins.

Guey Chuen (Oscar) Perng, Ph.D. Associate Professor of Pathology and Laboratory Medicine gperng@emory.edu Pathogenesis of chronic virus infections, focusing on the early immune events upon viral-host contacts. Three programs are initiated to tackle the mechanisms by which diseases developed in the course the host responses to the virus infections. Herpes Encephalitis: HSV-1 can cause encephalitis in infected animals and humans. Although herpes encephalitis is rare in adults, it affects 2-5% of infected infants and is therefore of significant clinical importance. Following peripheral infection, HSV-1 establishes latency in neurons of the infected host. Sporadically, the latent virus resurfaces to the sites of initial infection, causing recrudescent disease. The only gene that is readily detectable during neuronal latency is latency associated transcripts (LAT). We have shown that LAT locus is involved in neurovirulence in experimentally infected animals. Deletion of different portions of the LAT locus can alter the rate of death of infected animals due to encephalitis. Recently, we have cloned and demonstrated a gene, UOL (Upstream of LAT), locating in the LAT locus region plays a role in virulence in infected animals. Further studies indicated that the UOL interacts with an immune regulator factor, ICAM5, in the central nervous system (CNS). This interaction alters immune response in herpes infected animal brains. Identification of the mechanisms involved in the pathogenesis of encephalitis is of particular importance, given the current concerns of emerging infections and bioterrorism threat. Corneal Scarring: Herpes Stromal Keratitis (HSK) results from the infection of HSV-1 in cornea. HSV-1 infection, mainly recurrent, is a leading cause of corneal scarring and visual loss. HSK is characterized with tissue destruction, edema, opacification, corneal scarring, and neovascularization, and is thought to arise from an immunological inflammatory response in the stroma layer of cornea. However, no specific HSV antigens or peptides are physically demonstrated from the HSK corneas. Thus the cause of HSK is unclear. Recently, we reported that in HSV-1 induced HSK rabbit corneal buttons, an immediate early protein ICP0 was consistently detected in the water-soluble corneal extract and in the tears of infected animal eyes. To our surprise, the presence of ICP0l in the corneal was coincident with the loss of suggestive structural protein, Aldehyde dehydrogenase 1 (ALDH1). In wound injury in vivo animal models, the markedly reduced levels of ALDH1 correspond to the development of corneal opacity. By focusing on studying, identifying, and characterizing the molecular marker, HSV immediate early protein ICP0 and its relation to ALDH1, the pathogenesis of HSK may be comprehensible and may lead to develop a new treatment for the bothersome disease. Dengue Hemorrhagic Fever (DHF)/Dengue Shock Syndrome (DSS) Dengue fever, caused by infection with dengue virus, is not a new disease, but recently its serious emerging health threats, coupled with possible dire consequences including death, has aroused considerable medical and public health concern worldwide. The main obstacle for diagnosis is the dynamic spectrum of dengue illness ranging from asymptomatic to dengue hemorrhagic fever (DHF/dengue shock syndrome (DSS), characterized by thrombocytopenia and increased vascular permeability. One of the hallmarks in dengue disease is thrombocytopenia otherwise known as low platelet counts. The degree of thrombocytopenia appears well-correlated not only with the clinical severity of DHF but also with the activation of the complement system. During dengue virus infection, platelets may provide a wonderful shield for the virus from exposure and binding to neutralizing preexisting antibody. Interestingly, there are a few reports suggesting that dengue virus may associate with platelets, directly or indirectly through antibody. Recently dengue virus RNA has been detected in platelets isolated from dengue infected patients using RT-PCR techniques. The interesting point in these observations or reports is that the thrombocytopenia seen in DHF/DSS patients may not only be due to the destruction of platelets by the virus itself (direct cytotoxicity) but may also be due to the destruction of platelets following the binding of dengue specific antibodies to the virus infected platelets (immune mediated toxicity). It is also possible that platelets can serve as a reservoir for dengue virus replication; however this issue is a subject of further investigation. By investigation the role of platelets in the course of dengue virus infection may shed a new insight to the pathogenesis of dengue disease, new treatment, and a new strategy in vaccine development.

Richard K. Plemper, Ph.D. Assistant Professor of Pediatrics richard.plemper@emory.edu Blocking Paramyxovirus Entry and Replication Paramyxoviruses, enveloped, negative strand RNA viruses, cause significant morbidity and mortality worldwide. Members of this family include measles virus (MV), respiratory syncytial virus (RSV), human parainfluenza viruses (hPIV), and the recently emerged and highly pathogenic Nipah and Hendra viruses. It is the ultimate goal of my team to better understand paramyxovirus entry and genome replication, and apply this knowledge to the development of novel strategies to intervene with paramyxovirus infection. Investigating the molecular mechanism by which the viral fusion protein mediates membrane merger has led us to the structure-based development of a novel class of small-molecule MV entry inhibitors. Complementing these drug design efforts, we have developed an assay system for the automated discovery of entry and polymerase inhibitors. Implementation of this assay in a pilot screen has resulted in the discovery of a first in class non-nucleoside inhibitor of the viral RNA-dependent polymerase complex with high therapeutic potential. Current research focuses on a detailed understanding of the molecular mechanism of inhibition and, in an interdisciplinary collaboration with the Department of Chemistry, the development of both inhibitor classes to therapeutic leads. In addition to their therapeutic potential, we employ in parallel both inhibitor classes as innovative research tools through investigating patterns of viral escape from inhibition. Compiling the results of these approaches will advance our basic understanding of viral entry and replication, and ultimately allow the rational development of further optimized, highly potent antivirals.

Philip N. Rather, Ph.D. Associate Professor of Microbiology and Immunology prather@emory.edu Mechanisms of cell to cell signaling (quorum sensing) in bacteria. My lab is interested in the fundamental mechanisms of cell-to-cell signaling in Proteus mirabilis and Acinetobacter baumannnii. Both of these organisms are important human pathogens and cell-cell signaling influences factors required for virulence. My lab utilizes a variety of genetic and biochemical approaches to study this process. In particular, we are addressing the following areas: (i) identification of signals used for cell-to-cell communication, (ii) identification of genes are required for production of, and response to these signals, and (iii) investigating the role of cell-to-cell signaling in the physiology of each organism. website: The Rather Laboratory

Jyothi Rengarajan, PhD Assistant Professor of Infectious Disease jyothi.rengarajan@emory.edu Host-pathogen interactions in Tuberculosis We are interested in understanding how pathogens evade host immunity and how the immune response combats pathogens. Mycobacterium tuberculosis is one of the world's most successful human pathogens and is responsible for the deaths of up to 3 million people annually. The AIDS pandemic and Multi-drug resistant TB, further underscore the global public health challenge that TB presents. Developing vaccines and better therapeutics for TB is thus an important goal in our research efforts. The major questions that we seek to address in the lab are: How does M. tuberculosis survive in the host? Why does the host fail to eliminate M. tuberculosis? A fundamental concept that encompasses both these questions involves the M. tuberculosis-macrophage interface. Macrophages are central to host defense against microbes, but M. tuberculosis has evolved to evade their anti-microbial functions. We have used functional genomics to comprehensively determine the genome-wide requirements for M. tuberculosis survival and adaptation in macrophages by identifying mutants with defective intracellular growth. These studies also highlighted genes that are critical for pathogen survival and adaptation to the host, for example, a cell envelope-associated protease that modulates host innate immune responses. We are investigating the molecular and biochemical basis for protease function and have identified potential substrates using mass spectrometry-based proteomics approaches. Other projects in the lab are focused on dissecting the molecular pathways involved in the host innate immune response to infection in macrophages and dendritic cells. We also have ongoing interests in understanding mechanisms of drug resistance in mycobacteria and identifying targets for new chemotherapeutics. In the long term, we are interested in translating lab-based findings to human population-based settings of tuberculosis infection. Human studies are important for understanding mechanisms underlying host susceptibility, latent infection and protective immunity.

Raymond F. Schinazi, Ph.D., DSc (hon) Professor of Pediatrics and Director, Laboratory of Biochemical Pharmacology rschina@emory.edu Multidisciplinary antiviral research is aimed at discovering agents that could be used for the treatment HIV infections. The major research emphasis of the Laboratory of Biochemical Pharmacology is in two medically important areas. First, the group focuses on the development of antiviral agents for the treatment of infections caused by human immunodeficiency viruses, and hepatitis viruses. Work involves molecular modeling, synthetic, biochemical, pharmacological, and molecular approaches, including gene therapy and site directed mutagenesis. The main objective is to develop compounds for the prevention and treatment of these important diseases. Areas of particular interest include the characterization of drug-resistant virus variants and ways to overcome resistant viruses using combinations of drugs. Four compounds developed by this group have gone on to advanced clinical studies, and three have already been approved by the FDA for the treatment of HIV-1 infections. The multidisciplinary antiviral research is aimed at discovering agents that could be used for the treatment HIV infections, and modalities aimed at preventing the development of drug-resistant viruses. Current research is in the fields of HIV, SIV, HBV, HCV, herpesviruses, and cryptosporidium. The ongoing work is primarily funded from a VA Merit Award; the NIH sponsored Emory University Center for AIDS Research (CFAR), several NIH grants.

June R. Scott, Ph.D. Charles Howard Candler Professor of Microbiology and Immunology scott@microbio.emory.edu Molecular mechanisms of bacterial virulence; control of gene expression in bacteria. We are using molecular biological and microbial genetic techniques to study the molecular mechanisms of bacterial pathogenesis. Currently, we are focusing on the group A streptococcus (GAS, S. pyogenes), an important human pathogen that causes many types of diseases ranging from strep throat to necrotizing fasciitis and toxic shock syndrome. Because of the variety of different syndromes caused by this bacerium, we are investigating the regulation of expression of its major virulence determinants. We have developed the genetic tools (transposons, regulatable promoters) to ask about regulation and are using mouse models to assess virulence. The hope is that a greater understanding of the disease process will lead to improved approaches to prevention. The second major focus in the lab is the study of the hairlike structures, called pili, on the bacterial surface that are required for attachment to the human host. Currently, we are studying the mechanisms of assembly of these structures in the GAS, a Gram-positive organism. Because pili in Gram-positive bacteria were only discovered recently, little is known about them. Pili represent a potential target for intervention that might prevent disease because they seem to be needed for the first step in infection, i.e. colonization of the host. In addition, a better molecular understanding of the assembly process of these pili should enable them to be engineered to serve as vaccine vectors.

William M. Shafer, Ph.D. Professor of Microbiology and Immunology wshafer@emory.edu Genetics of antibiotic resistance; antimicrobial peptides; transcriptional regulation of gene expression; mechanisms of bacterial pathogenesis. We are interested in the molecular mechanisms of bacterial pathogenesis. In particular, research in our laboratory seeks to understand how bacterial pathogens evade both classical antibiotics and host antimicrobial compounds. We are particularly interested in the role of efflux pumps in bacterial resistance to antimicrobials. We study how genes encoding efflux pumps in Neisseria gonorrhoeae and Neisseria meningitidis are regulated at the level of transcription and how such regulatory processes impact pathogenesis. With the gonococcus, we are also interested in how phase-variable expression of certain genes impacts resistance to innate host defense mechanisms, particularly the serum complement system. We are also interested in the mechanisms by which antibacterial peptides produced by white blood cells and certain epithelial cells that line mucosal surfaces exert their activity. We have studied the structure-function relationships of a number of peptides and have constructed mutant strains of Staphylococcus aureus that display decreased susceptibility to their killing activity. We are now characterizing the bacterial genes that seem to modulate bacterial susceptibility to these host-defensive peptides. website: The Shafer Laboratory

Thomas M. Shinnick, Ph.D. Adjunct Professor of Microbiology and Immunology Chief, Tuberculosis/Mycobacteriology Branch, NCID of CDC tms1@cdc.gov Molecular genetic analysis of Mycobacteria. Tuberculosis and leprosy are important human disease that afflict more than 50 million individuals world-wide. The etiologic agents of these diseases are Mycobacterium tuberculosis and Mycobacterium leprae, respectively. Both of these mycobacteria are intracellular pathogens that grow within cells of the host immune system, primarily macrophages. Relatively little is known about the genes and gene products required for intracellular survival. Our research in this area concentrates on development and application of biophysical and genetic tools and strategies to identify mycobacterial genes that play roles in intracellular survival and replication. Current projects include using promoter-trap vectors and microarray hybridization approaches to identify differentially expressed genes. We are also taking advantage of the recently published genome sequence of M. tuberculosis to direct studies to characterize gene expression in tubercle bacilli. Two-component global regulatory systems and sigma factors are being studied to elucidate details of the regulation of gene expression and characterize patterns of gene expression. The ultimate goal is to elucidate the mechanisms that underlie the transition from an active infection to a latent infection and from a latent infection to an active infection.

Byeongwoon Song, Ph.D. Assistant Professor of Pediatrics bsong4@emory.edu HIV replication and cellular restriction Retroviruses encounter dominant post-entry restrictions in the cells of particular species. Human immunodeficiency virus type 1 (HIV-1) infection is blocked in the cells of Old World monkeys and simian immunodeficiency virus (SIV) infection is blocked in most New World monkey cells. TRIM5alpha is one of the key host factors restricting retroviral infection. We would like to understand the mechanisms of antiviral activity of TRIM5alpha protein, to identify cellular factors interacting with TRIM5alpha, and to determine the role of molecular chaperones in viral replication and cellular restriction. The outcome of this study will lead to an improved animal model of HIV/AIDS pathogenesis and reveal new antiretroviral targets.

Paul Spearman, M.D. Professor of Pediatrics and Microbiology and Immunology paul.spearman@emory.edu HIV assembly, trafficking of viral proteins, HIV vaccines. The Spearman laboratory focuses on HIV assembly, HIV pathogenesis, and immune responses relevant to HIV vaccine development. The HIV Gag protein forms the shell of the developing virion, and must traffic to its site of assembly through interactions with specific cellular pathways. Endosomal trafficking plays a prominent role in HIV assembly. We have described the interaction of Gag with the AP-3 adaptor complex, and are defining the role of this interaction in productive trafficking of Gag. The role of vesicular trafficking of Gag along microtubules is under intensive investigation at present. The form of Gag that interacts specifically with adaptors and regulators of vesicular trafficking is being dissected using mutants of Gag that fail to form multimers or fail to interact with cellular trafficking factors. The viral Vpu protein assists in particle release through overcoming a host cell restriction. The identification of this cellular restriction factor is essential to understanding this mechanism, and is a focus of the laboratory. Neutralizing antibodies directed against HIV can be elicited by vaccination, but lack breadth of activity against diverse isolates. The basic mechanisms of neutralization of HIV must be better understood in order to overcome this problem. We are dissecting the B cell repertoire that develops in infected individuals, and developing novel monoclonal antibodies from humans and from immunized mice in order to better understand the basis of HIV neutralization.

Samuel H. Speck, Ph.D. Georgia Research Alliance Endowed Professor of Microbiology and Immunology sspeck@emory.edu Pathogenesis of gamma-herpesviruses and development of lymphoma and other cancers. The research in my lab focuses on 2 gamma-herpesviruses, Epstein-Barr virus (EBV) and murine gamma herpesvirus 68 (gHV68). A major property of all herpesviruses is their ability to persist for life in the infected individual. The gamma-herpesviruses are known to latently infect either B or T lymphocytes, and to be associated with the development of lymphoma and lymphoproliferative diseases. Our major interests are to understand: (i) how these viruses regulate viral gene expression during latency; (ii) how they modulate and avoid the host immune response; and (iii) how they switch from a latent infection to replication of the viral genome (referred to as reactivation), a process that is essential for propagation of these viruses to uninfected individuals. EBV is the etiologic agent of infectious mononucleosis and is closely associated with the development of Burkitt's lymphoma, nasopharyngeal carcinoma, 30-50% of Hodgkin's disease, and 50% of lymphomas that arise in immunosuppressed individuals (e.g., transplant patients and AIDS patients). Our research on EBV focuses on tissue culture models that recapitulate the various EBV genetic programs. The information gained from these studies is then employed to address the behavior of EBV in infected individuals. However, because there are no small animal models for studying EBV pathogenesis, we use gHV68 infection of mice to address specific issues of the host response to gamma-herpesvirus infection. The advantage of the latter model is that both the host and pathogen can be genetically manipulated to address fundamental aspects of host-pathogen interactions. gHV68 infection of mice causes several different chronic diseases in immunocompromised mice, including a severe vasculitis that affects the great elastic arteries and lymphoproliferative disease. We are currently identifying gHV68 genes involved in establishing and maintaining viral latency, as well as those involved in the development of chronic disease. In addition, we are actively characterizing the host response to viral infection to address how viral latency and persistent infection is controlled.

David A. Steinhauer, Ph.D. Assistant Professor of Microbiology and Immunology steinhauer@microbio.emory.edu Functions of the influenza hemagglutinin in host cell entry; influenza assembly. We are interested in how influenza viruses get into host cells. The research focuses on structure/function studies of the viral hemagglutinin glycoprotein (HA) to understand how receptor binding and membrane fusion are mediated at the molecular level. The goal is to relate the mechanistic properties of these fundamental functions to the basic biology of influenza viruses with respect to replication characteristics, host range, adaptation, and potential to impact on human disease. website: The Steinhauer Lab

David S. Stephens, M.D. Director, Division of Infectious Diseases, Department Of Medicine Stephen W. Schwarzmann Distinguished Professor of Medicine Executive Associate Dean for Research, Emory University School of Medicine dstep01@emory.edu Genetic basis and regulation of bacterial virulence components; Innate Immunity Our laboratory is focused on genetic determinants of bacterial pathogenesis in Neisseria meningitidis and Streptococcus pneumoniae (important causes of meningitis and bacteremia) and other bacterial pathogens, on the discovery and development of bacterial vaccines and on the activation of the human innate immune system by bacterial ligands. These studies include the molecular mechanisms of attachment, colonization and invasion of human mucosal surfaces by pathogenic bacteria, conjugative transposons and role of transposons in bacterial virulence and antibiotic resistance and endotoxin structure and the interactions with MD-2 and TLR4. We are examining the genetic, structural and pathogenic basis of meningococcal lipopoly(oligo)saccharide, and meningococcal capsule and the role these ligands play in innate immune recognition. A better understanding of how pathogenic bacteria cause disease and engage the immune system is needed for new strategies for the design of vaccines and vaccine adjuvants that will protect against serious bacterial infections.

Yih-Ling Tzeng, Ph.D. Assistant Professor of Medicine ytzeng@emory.edu Regulatory mechanisms of gene expression; meningococcal pathogenesis. The long-term goal of my research is to elucidate the regulatory mechanisms of virulence determinants in meningococcal pathogenesis and understand the signal transduction pathways by which meningococci sense and interact with the host. By directly studying these issues, my group continues to provide a fuller knowledge base for the development of vaccine strategies and therapeutic interventions. Currently, we focus on a novel two-component signal transduction system shown to be a global regulator mediating the expression of meningococcal virulence determinants including the structural modification of endotoxin, iron uptake and assimilation, and protein folding machinery. Using genetic, biochemical and molecular biological strategies we hope to provide not only a broad view of the regulatory scope of this important signal transduction system, but also a detailed understanding of both the molecular regulatory mechanisms and the interaction of this network with other regulatory control of gene expression. Furthermore, efforts are also focused on identifying the host signal that activates this two-component regulatory system.

David Weiss, Ph.D. Assistant Professor of Infectious Disease david.weiss@emory.edu Microbial pathogenesis and host defense/Francisella Our lab is interested in understanding mechanisms of bacterial pathogenesis and the host’s response to infection. We are currently focusing on the Gram-negative bacterial pathogen Francisella tularensis. F. tularensis is highly infectious and causes tularemia, a potentially life-threatening disease in humans.  Critical to Francisella’s pathogenesis are its ability to replicate within macrophages, the primary niche for replication in vivo, and to subvert the host immune system.  Unfortunately, relatively little is known about which genes Francisella uses to modulate host defenses. In order to identify critical Francisella virulence genes, we recently employed a powerful global in vivo negative selection screen.  This approach resulted in the identification of 164 genes that are required for virulence, 44 of which appear to encode novel virulence factors. Study of mutants lacking two of the novel genes we identified revealed that they act to suppress the macrophage cell death response.  We previously described that this pathway, dependent on the host inflammasome complex containing the proteins Caspase-1 and ASC, plays an important role in host defense against Francisella infection.  This highlights how Francisella attempts to suppress critical host defenses, and the molecular tug-of-war that takes place between Francisella and the host during infection. Future work will elucidate the roles of other novel Francisella virulence factors as well as identifying the host defense pathways that they modulate.  One area of focus will be determining if and how Francisella subverts dendritic cell function to evade the immune response.  Our work will allow us to gain insights into Francisella pathogenesis and host-pathogen interactions, while leading us towards an F. tularensis vaccine and the identification of critical targets for therapeutics to treat tularemia.

Elizabeth Wright, Ph.D. Assistant Professor of Pediatrics, Division of Infectious Diseases erwrigh@emory.edu Cryo-electron microscopy methods for the structural examination of hos-pathogen relationships in order to develop novel vaccines and therapeutics.. HIV-1: It has already been demonstrated that cryo-EM methods have substantially increased our understanding of the basic structure and the proteolytic maturation of HIV-1. We hypothesize that one major factor limiting the development of HIV-1 therapeutics is our incomplete understanding of structural aspects of the viral life cycle, including Env-mediated fusion, viral assembly and trafficking, and viral maturation. Information gathered from probing the morphology and structure-function relationships that exist between the virus and cells in vivo will provide a basis for further biochemical, structural, and vaccine development studies. First, we will explore, by cryo-ET, HIV-1 maturation after the virus has budded from the host cell. Our main goals are to understand: 1) The process of viral maturation and the structural intermediates associated with the proteolytic cleavage of Gag, 2) The placement, association, and anchor point of the Envelope (Env) glycoproteins within the Gag polyprotein lattice of the immature virus, and 3) The localization of the Env glycoproteins in the mature virus. This structural information will provide a foundation from which we will pursue the development of novel antiretroviral agents that specifically target structural intermediates within the maturation pathway, the interactions between the Gag domains and Env glycoproteins during assembly, and Env glycoprotein structural intermediates. We will develop and employ correlative microscopy methods to define the pathways of HIV-1 viral assembly within cells. HIV-1 has adapted to the range of cells it infects by developing multiple pathways for Env-mediated infection, assembly, and budding. Fluorescence microscopy has significantly advanced our understanding of HIV-1 trafficking and assembly. However, its limited resolution makes it difficult to examine the intricate structural contacts, arrangements, and localizations made between the virus and the host cell. Our goal is to merge the spatial and structural information attainable by fluorescence microscopy and cryo-EM/cryo-ET to clarify our understanding of the viral life cycle. Paramyxoviruses: Protein-mediated membrane fusion at neutral pH is essential for eukaryotic cell organization and is employed by a variety of viral families to gain cell entry. Despite its major importance, many of the mechanistic principles that govern the organization of metastable fusion complexes and their coordinated refolding remain poorly understood. In collaboration with Prof. Richard K. Plemper (Emory University Division of Pediatric Infectious Diseases), the envelope proteins of measles virus (MV), an archetype of the paramyxovirus family, will be studied as a model system for viral fusogenic membrane glycoproteins. This project will address two basic questions: What is the spatial organization of paramyxovirus glycoprotein hetero-oligomer complexes in the native, metastable prefusion conformation? How does receptor binding affect this organization? We hypothesize that prefusion MV glycoprotein hetero-oligomers assume a defined, tightly packed spatial organization on the surface of infectious particles. We will probe the geometry of native, hydrated hetero-oligomers in situ through cryo-electron tomography (cryo-ET) of purified MV particles. Available crystal structures of envelope glycoprotein will be superimposed within the reconstructed 3D volumes to achieve high-resolution hetero-oligomer pseudoatomic structures. In addition, treatment of purified particles with soluble receptor molecules prior to cryo-ET will elucidate the effect of receptor binding on the geometry of these structures. Technology Development: In addition to biological projects, I am interested in cryo-ET method development as related to the study of biological systems. I have coauthored an article about the capabilities of the 'flip-flop' rotation system for the collection of dual-axis tomograms at cryo-temperatures, two papers on the effects of both liquid nitrogen and helium cooling on biological samples, and a paper regarding cryo-ET sample preparation using the FEI Vitrobot. My current interests are in developing correlative microscopy methods for the exploration of structure-function relationships of host-pathogen systems from the cryo-ET macromolecular resolution of ~2-4nm to the gross level of the whole cell at ~200 nm resolution.

Guang-Jer Wu, Ph.D. Associate Professor of Microbiology and Immunology wu@microbio.emory.edu Molecular mechanism of melanoma and prostate cancer metastasis and development of viral vaccines. UC18 (MEL-CAM/CD146), has been postulated to play an important pathogenic role in metastatic melanoma progression. To study its role in mediating metastasis, we have used RT-PCR to amplify and clone the human MUC18 cDNA gene and used RACE-RT-PCR to amplify and clone the mouse MUC18 cDNA gene. We have produced both recombinant proteins in a bacteria GST expression system and purified them for making polyclonal antibodies in chickens. We have also cloned these genes into a mammalian expression vector. We have transfected the expressible mouse cDNA gene into a murine melanoma cell line that does not express MUC18 and obtained G418-resistant clones that expressed high levels of MUC18. We tested the effect of expression of MUC18 on induction of lung metastasis in syngeneic mice by injection of these MUC18-high-expression clones via i.v. and via s.c. routes. We found that these high-expression clones induced efficient lung nodule formation (metastasis) via only the i.v. route, suggesting that MUC18 is important for metastasis. Surprisingly, we found the expression of MUC18 in three mouse melanoma cell lines have tumor suppression effect. We are in the process of studying the mechanism of induction of metastasis by MUC18 in vivo. We are also trying to identify the heterophilic ligand(s) and co-factors of MUC18. We also studied the expression of MUC18 in prostate cancer cell lines and tissues. We found that human MUC18 only expressed in metastatic prostate cancer cell lines, but not in the non-metastatic cancer cell line. Human MUC18 was not expressed in the normal prostatic acinar epithelial cells, or in BPH. But it was highly expressed in precancerous acinar epithelial cells of PIN and in the prostate cancer tissues as well as in metastatic lesions in lung and lympn node. Thus the level of MUC18 expression appeared to increase with increasing pathological grades. We have proposed that MUC18 may also mediate metastasis of prostate cancers. To test this hypothesis, we injected orthotopically(into the prostate gland)the M UC18- exprssing human prostate cancer LNCaP cells in nude mice. We found that increasing MUC18 expression increased the tumor take and metastasis of the cells from prostate gland to various organs (seminal vesicles, ureter, kidney,and peri-aortic lymph nodes. We thus provided evidence that MUC18 also plays an important role in causing metastasis of the human prostate cacner LNCaP cells in xenograft model. Currently we are also collaborating with Dr. Leland Chungââ‚â"¢s group on his bone metastasis xenograft model, and with Drs. Chris Gregory and Thomas Pretlow on their CWR22 xenographft model. We are also collaborating with Dr. Norman Greenberg on his TRAMP model and with Dr. Jeff Gordon on his neuroendocrine cells-derived prostate carcinoma transgenic mouse model. We are also collaborating with the members of the Emory Prostate Cancer Center on prostate cancer metastasis. We have also cloned the genomic copies of these genes that contain the 5'-flanking transcription regulatory sequences for studying transcription factors and signal transduction mediators that regulate their expression in normal versus cancer cells. We are also collaborating with other Emory faculty on developing cancer vaccines.