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Armenise-Harvard
Foundation Phd Program - 2002-2003 Pathology Pathology, the study of the nature of diseases, was first developed in Europe in the nineteenth century. In 1847, the field of pathology was introduced to the United States by faculty at Harvard Medical School. Over the last 150 years, the Harvard Medical School Department of Pathology has advanced the frontier of understanding the pathology and causes of human diseases. The Department provides research and training opportunities in a broad range of basic and medical sciences and in areas directly relevant to the study of human diseases and pathogenesis. The major areas of research include cancer biology, vascular biology, aging, experimental neuropathology, virology, and immunology. The Department's focus on the mechanisms of pathogenesis provide a unique opportunity to study the cell biology, physiology, molecular biology, and genetics underlying normal development and what goes awry in disease processes. Today, the Department of Pathology at Harvard Medical School is the largest of the six basic science departments. In addition to the 15 faculty located in the central department on the quadrangle on Longwood Avenue, there are approximately 200 additional research, teaching, and clinical faculty located at the Harvard-affiliated hospitals and research institutions. Department Website: http://www.hms.harvard.edu/pathol/index.html
The Benjamin laboratory works in experimental cancer research using the DNA tumor virus "polyoma" and its natural host, the mouse. The highly oncogenic mouse polyomavirus is amenable to study both in cell culture and in the mouse. This system provides opportunities to study genetic determinants of both virus and host as they affect tumor development in a variety of tissues. Current projects include (1) mechanisms of cell entry by the virus; (2) studies of viral determinants of cell transformation and tumor induction; (3) mechanisms of bypassing p53 and inducing genetic instability; (4) use of the virus to identify possible new tumor suppressor genes; and (5) tumor immunity and other effects of the mouse genetic background in determining susceptibility or resistance to tumor induction by the virus. The Benjamin lab currently has 6 postdoctoral fellows. Azad Bonni, Ph.D. Assistant Professor Department of Pathology Harvard Medical School Armenise Building 200 Longwood Avenue Boston, MA 02115 Tel: 617-432-4104 Fax: 617-432-0727 Email: azad_bonni@hms.harvard.edu Website: http://www.hms.harvard.edu/pathol/abonni.html The Bonni laboratory is interested in the intracellular signal transduction mechanisms that regulate cell survival and differentiation in the developing mammalian nervous system. The lab is also interested in how aberrances of these signaling mechanisms contribute to neoplastic and neurodegenerative diseases of the nervous system. In studies designed to characterize the mechanisms that control cell differentiation, the lab has employed a primary in vitro cell culture system that recapitulates aspects of development in the rat cerebral cortex. Bonni has found that CNTF-related cytokines impose a glial fate on precursor cells of the developing cerebral cortex by inducing their differentiation into astrocytes and inhibiting differentiation into neurons. In other studies, Bonni has begun to characterize the signaling pathways by which extracellular factors promote the survival of neurons in the developing central nervous system. He has found that the Ras-MAPK signaling pathway mediates the trophic effects of the neurotrophin BDNF in rat cerebellar granule neurons by a dual mechanism that comprises the direct inhibition of the cell death machinery and the induction of pro-survival genes. An important area of biomedical research in the future will be the characterization of the mechanisms by which pathogenic insults trigger neuronal degeneration in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. These results often lead to cell death. Understanding how neurons die under these circumstances will likely yield clues as to how pathogenic insults induce changes in the normal physiology of the neuron that underlie the neurodegenerative process. As a first step to understanding what these changes might be, the lab plans to develop in vitro cellular models of neuronal degeneration. These models will be useful for identifying the particular alterations in the cell death machinery that occur in degenerating neurons. Then researchers will be able to use these changes to trace in reverse the biochemical events that are induced by pathogenic insults. Background information on the approaches used to study the signaling mechanisms that regulate cell specification and cell survival in the central nervous system can be found in Science 1997, 278:477 and Science 1999, 286:1358. The Bonni lab has 2 postdoctoral fellows and 2 graduate students.
The Dorf laboratory focuses on the mechanisms controlling inflammatory responses especially in the central nervous system. Leukocyte infiltration into the tissues is an essential feature of inflammation. Cell migration into inflamed sites is the result of a complex set of molecularly distinguishable signals. Inflammatory mediators released at the focus of tissue injury attract circulating leukocytes. One family of chemoattractant cytokines, termed chemokines, contributes to the specificity of the leukocyte infiltrate. The dramatic increase of chemokines during inflammatory reactions results in the selective recruitment of specific leukocyte populations into inflamed tissues. Chemokines induce leukocyte migration and activation by binding to specific receptors. These receptors belong to a family of G protein-coupled receptors that are differentially expressed on leukocytes and various other target cells including glial cells (astrocytes and microglia). Some chemokine receptors are constitutively expressed while products of the inflammatory process regulate the expression of others. This laboratory has cloned and characterized several murine chemokines and chemokine receptors involved in the normal and pathological responses. Particular attention is focused on those chemokines that are expressed in the central nervous system including those associated with chronic inflammatory autoimmune and infectious diseases. The blood-brain barrier normally prevents leukocyte transmigration into the central nervous system. The lab investigates the requirements leading to breakdown of the blood-brain barrier in an experimental model of multiple sclerosis and in chemokine transgenic mice. The results to date indicate that the actions of chemokines on astrocytes play critical roles in maintenance or disruption of the blood-brain barrier. Future studies are designed to investigate the genetics and biochemistry of chemokine-astrocyte interactions. The Dorf lab has 5 postdoctoral fellows and one graduate student.
The Forrester laboratory is interested in understanding the ground rules that govern tissue specific gene expression. The lab is exploring how different types of transcription controlling elements functionally cooperate to constitute a complex "master" regulatory element termed a Locus Control Region (LCR). LCRs, identified for a number of genetic loci, are composite elements sufficient to confer appropriate gene expression patterns in transgenic mice. LCRs contain classic enhancers which stimulate promoter function in cell culture transfection experiments, but cannot, by themselves, establish promoter function during normal development. Among the best examples of this is the Immunoglobulin (Ig) heavy chain intronic enhancer region, which can confer developmentally correct expression in transgenic mice only when flanked by nuclear matrix attachment regions (MARs). More recently, the lab has demonstrated that the MARs are a type of ontogeny-specific regulatory element. Unlike transfection experiments, during early vertebrate development DNA becomes heavily methylated. Genes subsequently selected for activation in differentiating somatic cells become, at least partially, demethylated consistent with a role for DNA demethylation in cell type specific gene expression. To examine this more directly, researchers in the lab introduced DNA, after methylation, into cells in culture. Interestingly, they found that long-range interactions between the Ig enhancer and promoter are inhibited in these methylated genes. However, when the enhancer is placed immediately adjacent to the promoter, methylation has no effect on enhancer-dependent stimulation. They conclude that methylation does not repress the functionality of the enhancer at the level of binding transcription. Rather, methylation appears to selectively block enhancer action at a distance. Using this approach, researchers in the lab have found that the MARs antagonize methylation-mediated repression of long-range enhancer function such that a promoter can now be activated by a distally located enhancer. These observations suggest that distance effects are regulated negatively by methylation, and positively by MARs. Using this system as a paradigm, the lab is seeking to identify both the sequences within the MARs and the nuclear factors which act at those sites to facilitate long-range effects. The Forrester lab has 2 postdoctoral fellows and 1 graduate student.
Research in the Gill laboratory is directed toward understanding how specific patterns of gene expression are established during development of the nervous system. To achieve this goal, researchers in the lab are investigating representative promoter elements, transcription factors, and signaling pathways important for development and function of the nervous system. In one project, researchers in the lab are investigating the activity of a protein, CREG, which promotes neuronal differentiation of human NTERA-2 embryonic carcinoma cells. Current efforts are designed to elucidate the signal transduction pathway by which CREG induces changes in gene expression concomitant with differentiation. The laboratory is also investigating the mechanisms regulating expression of p35 and p39, the neuronal-specific activators of cycling dependent kinase 5 (cdk5). P35 and p39 expression levels determine Cdk5 kinase activity, which is required for normal development and function of the nervous system. Understanding the mechanisms that regulate p35 and p39 expression may yield insight into the pathways that regulate neuronal migration, neuritis outgrowth, and synaptic function in normal development, and may possibly provide new information about the pathogenesis of neurodegenerative diseases. Specific graduate student projects include: (1) identification and cloning of the CREG receptor; (2) investigation of CREG effects on cell survival and differentiation; (3) analysis of changes in gene expression induced by CREG; (4) identification and cloning of transcription factors that determine cell-type specific expression of p35 and p39; and (4) analysis of the signaling pathways that regulate p35 expression levels in differentiated neurons. The Gill Lab has 2 postdoctoral fellows and 1 research associate.
The Hinds laboratory focuses on the role of the retinoblastoma protein (pRB) pathway in differentiation and cancer. The retinoblastoma protein acts to control proliferation at least in part by regulating transcription of genes required for DNA synthesis. Recent work demonstrates that pRB can also promote the synthesis of gene products involved in generating the differentiated phenotype of a number of different tissue types. Furthermore, pRB is likely to play a role in enforcing the permanent cell cycle withdrawal associated with terminal differentiation and the tumor-suppressive process of senescence. The function of pRB in these systems is regulated by the activity of D type cyclins in combination with cdk4 or cdk6. These cell cycle regulators are often found to be hyperactivated in tumors, thus achieving an oncogenic property that acts in opposition to pRB. Using biochemical and animal model systems, the Hinds lab is investigating the role of pRB in bone cell differentiation and senescence. In addition, the lab is exploring the specific roles of cyclin D1, cdk4 and cdk6 in differentiation and cancer of several cell types. The group has recently found that pRB can regulate cell cycle exit in bone cells by inducing the expression of p27, a negative regulator of cdk2, and that pRB also has a specific role in activating the bone transcription factor CBFA1. The lab is currently exploring the mechanism of p27 induction by pRB and consequent senescence. The lab is also pursuing the intriguing question of how pRB activates bone-specific transcription and studying the biological consequences of pRB loss in the bone cells of developing mice. To explore the role of cdk4 and cdk6 in specific cancers, researchers in the lab have identified a number of proteins that interact specifically with either cdk4 or cdk6. Several novel cdk6 interactors that have been identified suggest a role for cdk6 in regulating the differentiated phenotype directly, in addition to a role in pRB regulation. Researchers are currently performing such studies in astrocyte and neuronal models, where cdk4 and cdk6 may have important roles in tumor formation, and in the oral epithelium, where cdk6 activity is specifically increased in cancer cells. The combination of biochemical and biological approaches to understanding the function of each of these proteins in differentiation and cell cycle dysregulation in tumor cells affords a selection of research opportunities in cell cycle control, development, and cancer. The Hinds lab has 4 postdoctoral fellows and 4 graduate students.
Research in the Howley lab focuses on the molecular biology of the papillomaviruses and their role in carcinogenesis. Compelling evidence associates several specific types of the human papillomaviruses (HPVs) with human cervical cancer. These "high risk" HPV types, such as HPV 16 and HPV 18, encode two oncoproteins, E6 and E7, which target the important cellular growth proteins p53 and pRb, respectively. Researchers in the lab have previously shown that E6 promotes the ubiquitination and degradation of p53, a process that is mediated by a cellular protein called the E6 Associated Protein (E6AP). The lab studies the basis of ubiquitin substrate recognition and, in particular, the regulation of E6AP. Specific projects in the lab involve (1) the identification of cellular proteins that E6AP normally targets in cells, (2) the identification of other cellular targets of the PV E6 oncoprotein, (3) the study of how the PVs evade both cellular innate and acquired immune responses, and (4) an analysis of the PV E1 and E2 regulatory proteins that are involved in viral DNA replication and in viral transcriptional regulation. The Howley lab has 8 postdoctoral fellows and 4 graduate students.
The Munger laboratory studies fundamental cellular processes such as cell cycle control, cellular differentiation, and cell death and their dysregulation in human disease and cancer. Research focuses on two main topics: 1) molecular mechanisms of HPV-induced cervical cancer, and 2) TID1, a human homolog of the Drosophila tumor suppressor gene tumorous imaginal discs. Possible research projects include (1) determining the biochemical basis for the ability of the human papillomavirus E7 oncoprotein to induce centrosome-associated mitotic abnormalities and genomic instability, and (2) analyzing the cellular targets of the pro- and anti-apoptotic splice forms of TID1. The Munger lab has 3 postdoctoral fellows and 5 graduate students.
Research in the Ploegh laboratory focuses on the cell biology and biochemistry of antigen presentation. In particular, strategies used by pathogens to avoid detection by cytotoxic T cells are a major topic of interest. The lab is pursuing the use of organic-synthetic methods to produce small molecules useful in the manipulation of the above processes, particularly the ubiquitin-proteasome pathway. We are implementing mass spectrometry-based methods to aid in the identification, by sequence analysis, of proteins modified by newly developed inhibitors. Applications for research projects from immunologists, cell biologists, and organic chemists interested in cell biology are welcomed. The Ploegh lab has 10 postdoctoral fellows and 6 graduate students.
Email: yshi@hms.harvard.edu The Shi laboratory is interested in the role of transcription factors and cofactors in development and differentiation, and the mechanisms by which they regulate transcription in vivo. The lab uses two model systems -- mouse and C. elegans -- to address relevant questions. Using the C. elegans, the lab studies chromatin remodeling activities in cell fate determination and differentiation of specific cell lineage. The lab is particularly interested in histone acetylases and deacetylases. Research in the lab showed that histone deacetylase, HDA-1, is essential for embryogenesis and that HDA-1 is also involved in gonadogenesis and perhaps germ cell development. The lab is now determining whether histone deacetylase HDA-1 plays a role in transcriptional silencing in germ cells. The lab uses mouse and cell culture to study transcription factor Yin Yang 1 (YY1), which was initially isolated by us as a target of adenovirus E1A oncoproteins. The importance of YY1 is highlighted by the fact that E1A regulates the activity of YY1, and this regulation appears to be important for E1A to induce oncogenic transformation and to inhibit differentiation. Therefore, insights into YY1 function and mechanism of action in vivo are likely to enhance understanding of cell growth control and tumor genesis. To study YY1 in later development, lab researchers have recently generated ES cells carrying a conditional allele of YY1 and are in the process of generating mice carrying conditional alleles of YY1. As a complementary approach, they plan to isolate a variety of YY1 deficient cells in which to conduct in-depth biochemical and molecular studies of YY1 in cell growth and differentiation. With these cells, they will also identify in vivo YY1 target genes and investigate molecular mechanisms by which YY1 activates and represses genes in their natural chromosomal locations. Lastly, the lab is studying a protein termed par-4 (prostate apoptosis response), which is a suppressor of WT1 and appears to be involved in sensitizing cells to apoptotic signals. The Shi lab has 8 postdoctoral fellows.
Research in the Sinclair laboratory is aimed at understanding the aging process at a molecular level. Is aging due to a multitude of processes or perhaps a key few? What are the limiting weaknesses that lead to deterioration and eventual death? Are aging and cancer related? The Sinclair lab uses model systems to rapidly investigate fundamental cellular processes related to aging. The lab then extends these findings to the mammalian system to determine their relevance to human disease. Aging has been proposed to result from the limited number of cellular divisions human cells undergo before their telomeres shorten to a critical length. Cells can avoid senescence by activating telomerase-independent telomere maintenance pathways (ALT), a key step in the development of many tumors. Important clues about the cause of aging may be gained from inherited human diseases that appear to accelerate aging such as Werner syndrome, which is characterized by gray hair, wrinkled skin, atherosclerosis, osteoporosis, and certain types of cancer. The disease is due to mutations in a single gene, WRN, which encodes a DNA helicase of unknown function. The Sinclair lab aims to gain an understanding of Werner syndrome and normal human aging by determining the cellular function of WRN and related helicases. Possible research projects include an investigation of the yeast homologue of WRN, Sgs1, a DNA helicase required for genome stability and the longevity of individual yeast cells. The Sinclair lab has recently shown that Sgs1 is required for telomere maintenance as well as the recovery of cells from senescence via an ALT pathway. These findings suggest that, although RecQ-helicases can delay age-related diseases, they ironically may also assist in the proliferation of tumorigenic cells. This is good evidence for the idea that aging and cancer are merely two sides of the same coin. The Sinclair lab is also screening for genes that influence life span, using yeast and C. elegans as model systems. The life span of most organisms can be significantly extended by limiting the number of calories the organism consumes, in a dietary regime known as caloric restriction (CR). For example, rats fed approximately 30% normal calorie intake live up to 40% longer and show less age-associated physiological deterioration. The lab's goal is to identify genes and small compounds that mimic CR and extend life span - without having to undergo strict dieting. Researchers have recently identified numerous genes that extend life span in yeast and will soon test these in C. elegans. A third aspect of the lab's research involves the study of a human gene called SIRT1 that extends lifespan in both yeast and C. elegans. The Sinclair lab has 2 postdoctoral fellows and 3 graduate students.
The Tsai laboratory studies programmed cell migration in the histogenesis of the mammalian central nervous system. The cytoarchitecture of the cerebral cortex and cerebellum relies on the distinct modes of migration of multiple cell types in different development stages. A small protein ser/thr kinase Cdk5 in conjunction with its regulatory partners, p35 and p39, plays an indispensable role in these processes. Potential research projects include (1) determining whether Cdk5/p35 interacts with components of the reelin signaling pathway; (2) identifying proteins phosphorylated by Cdk5 after neurotoxic treatment; and (3) exploring cell surface events that activate Cdk5 activity. The Tsai lab has 8 postdoctoral fellows and 5 graduate students.
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