1995 — 1999 |
Cesarman, Ethel |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Kaposis Sarcoma Associated Virus in Aids/Lymphomas @ Weill Medical College of Cornell Univ
The principal objective of the studies proposed here is to determine the role of the recently identified Kaposi's sarcoma-associated herpesvirus (KSHV) in the pathogenesis of AIDS-associated body cavity based lymphomas (AIDS-BCBLs). Since this virus is present in all AIDS-BCBLs examined thus far, and no other type of lymphoma, we will specifically study the elements of KSHV which might be responsible for transformation as well as for the unusual phenotype of these lymphoid neoplasms. Because the portions of KSHV which have been cloned and sequenced thus far have shown homology and collinearity with Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), we will take advantage of methodologies previously established for the study of the role of these viruses in the development of malignant lymphomas. Specifically, we will 1) determine the presence and type of transforming genes in KSHV. This will be achieved by cloning and sequencing larger portions of the KSHV genome in order to obtain genes homologous to those in EBV and HVS which are relevant in lymphoid transformation. We will 2) determine the ability of KSHV to infect lymphoid cells in vitro. In order to do this, we will use methods previously established for other herpesviruses, i.e. EBV, such as co- cultivation of lethally irradiated infected cells with the target cells. After transmission is achieved we will 3) determine the oncogenic effect of KSHV in lymphoid cells. For this purpose we will assess the phenotypic and biologic differences, including growth rate, serum requirements, growth in soft agar and tumorigenesis in nude mice, between the infected and uninfected cells. We will attempt to identify the phenotypic and biologic features of infected cells which may be related to the growth pattern of AIDS-BCBL, that is, as malignant effusions. Subsequently, we will 4) investigate the genes responsible for the effect(s) KSHV might have in lymphoid transformation. In order to do this, gene transfer experiments will be performed using genes homologous to those in EBV and KSHV which are already known to be relevant for lymphoid transformation. In the event that genes without homologies to EBV or HVS are identified, they will also be tested for possible effects in lymphoid transformation. Thus, we will take advantage of mostly "classic" methods as well as the understanding of similar viruses, to assess the role of KSHV in the pathogenesis of AIDS-BCBLs. This will lead to a better understanding of a novel human herpesvirus which appears to be playing a relevant role in the malignant transformation of a subset of AIDS-associated lymphomas.
|
1 |
1996 — 1999 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Kshv Putative Oncogenes in Aids Malignancies @ Weill Medical College of Cornell Univ |
1 |
1999 — 2001 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Kshv Transformation and Angiogenesis in Kaposis Sarcoma @ Weill Medical College of Cornell Univ
Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV 8), is invariably present in Kaposi's sarcoma (KS) lesions where it has been localized in the endothelial cells as well as in the spindle cells, which are thought to be of endothelial cell origin. We have been able to reproducibly infect primary human endothelial cells with KSHV, and obtained apparently immortalized endothelial cell cultures as a direct result of this infection. The KSHV-infected endothelial cells are transformed as defined by their anchorage independent growth, prolonged survival and telomerase activity. This provides the first direct demonstration that KSHV is an oncogenic virus, and probably represents the best in vitro system developed thus far to study the pathobiology of Kaposi's sarcoma. However, the mechanism of transformation utilized by KSHV appears to be different from that of other oncogenic viruses, since only a small proportion of the cells in these cultures retain the viral genome. Preliminary evidence has suggested that paracrine mechanisms play an important role in the long term survival induced by KSHV, but that the viral genome is necessary for full transformation. Our overall objective is to test this hypothesis by using in vitro infection of endothelial cells to analyze the mechanism(s) of transformation of endothelial cells by KSHV and the role of angiogenesis in this process. Specifically, we plan: (Aim number 1 )to characterize the paracrine mechanisms responsible for the long term survival of endothelial cells; (Aim number 2) to assess the direct effect of KSHV in transformation; (Aim number 3) to assess the HIV/KSHV interactions in endothelial cell cultures, and (Aim number 4) to develop a mouse model for the study of KS. The results of these experiments should allow us to better understand the process of infection and transformation by KSHV. The information gained will contribute to our understanding of the pathogenesis of Kaposis sarcoma, and will aid in the development of rational therapeutic and preventive approaches. These studies will also provide information that will enrich our general knowledge of viral oncogenesis.
|
1 |
2001 — 2005 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Kshv/Hhv 8 in Aids Lymphomas @ Weill Medical College of Cornell Univ
DESCRIPTION:Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is consistently present in primary effusion lymphomas (PELs). The specificity of this association suggests that KSHV plays an important role in the pathobiology of this lymphoid malignancy occurring more frequently in HIV-infected individuals. We were the first to describe this association, and to develop PEL cell lines, which are still the only efficient tool for viral propagation and isolation, and remain an important source of antigen for serologic assays. Our laboratory has also played a pivotol role in the understanding of the clinical, pathologic, and molecular characteristics of PELs. While much has been learned since the identification of KSHV in PELs, our understanding of this disease remains incomplete. We have collected and characterized a significant number of PEL specimens and cell lines, which will be used as a resource to assess the role of KSHV in the pathobiology of primary effusion lymphomas. KSHV contains multiple putative viral oncogenes, as they encode proteins that can affect cellular proliferation and survival. However, which of these are necessary for PEL development and maintenance remains completely unknown. Activation of the transcription factor NFkB is a likely target of KSHV infection, as it is a potent induced of genes involved in he proliferation and survival of lymphocytes, and an important target of the transforming genes of EBV and HLTV1. Our preliminary data indicates that NFkB is constitutively active in PEL cell lines and clinical samples, and its inhibition results in considerably decreased cellular survival. Therefore, we hypothesize that subversion of cellular signaling cascades by KSHV-encoded genes, and in particular activation of NFkB, is critical for KSHV lymphomagenesis. In addition, we hypothesize that among the KSHV-encoded proteins, vFLIP is responsible for most of the NF-kB activity observed in latently infected PEL cells, which will be tested in Specific Aim #1. Specific Aim #2 is to analyze the activation of the MAP kinase signal transduction pathways in PEL cells. We will determine the consequences of signaling leading to NF-kB and MAP kinase activation in the proliferation, survival, and phenotypic characteristics of PEL cells (Specific Aim #3). These studies should contribute to our understanding of the molecular mechanisms that are critical in KSHV lymphomagenesis and increase our knowledge of the pathobiology of PEL, a highly aggressive and still incurable type of AIDS-related malignancy.
|
1 |
2004 — 2008 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Kshv Vflip in B Cell Survival @ Weill Medical College of Cornell Univ
DESCRIPTION (provided by applicant): KSHV/HHV-8 is clearly etiologically associated with Kaposi's sarcoma. This virus can be found in the B cells of infected individuals, both in the circulation and mantle zones of lymph nodes. In addition it is present in B cells in a large proportion of multicentric Castleman's disease as well as in B cell lymphomas, specifically primary effusion lymphomas (PEL) and a subset of large cell non-Hodgkin's lymphomas in HIV-positive individuals not involving body cavities. While KSHV-infection is not sufficient for the development of these disorders, the specific association suggests that KSHV plays a role in their pathogenesis. We hypothesize that that vFLIP is a critical mediator of this oncogenic consequence of viral infection. In support of this hypothesis our preliminary data indicates that vFLIP activates NF-KappaB in B cells, that NF-KappaB activity is essential for the survival of PEL cells, and that vFLIP is largely responsible for the constitutive NF-KB activity seen in latently infected lymphoma cells. We propose that vFLIP protects cells from apoptosis by a two pronged effect on TNF-signaling pathways: first directly by interfering with the activation and function of the death-inducing signaling complex (DISC), and second indirectly by forming a life-inducing signaling complex (LISC) which leads to NF-KappaB activation, in turn inducing expression of anti-apoptotic genes. We will test this model and determine the role of vFLIP in the survival of B cells through the following specific aims: 1) Characterize the role of vFLIP in PEL cell survival; 2) Perform a structural and functional characterization of vFLIP activity in B cells; and 3) Assess vFLIP function in vivo. These studies will lead to a detailed understanding of the contribution of KSHV vFLIP to the survival of infected B cells and lymphomagenesis, and validate vFLIP as a therapeutic target for the treatment of primary effusion lymphoma and perhaps other KSHV-associated diseases.
|
1 |
2006 — 2007 |
Cesarman, Ethel |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Identifying Small Molecule Inhibitors of Kshv Vflip-Traf2 Interactions. @ Weill Medical College of Cornell Univ
[unreadable] DESCRIPTION (provided by applicant): The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is causally associated with the development of Kaposi's sarcoma (KS), some malignant lymphomas and multicentric Castleman's disease. KS remains the most common AIDS-related malignancy, and no curative approach exists. We have found that a protein encoded by KSHV, called vFLIP, is necessary for the survival of KSHV-infected lymphoma cells. There is also evidence that vFLIP is expressed in KS lesions, and can enhance the appearance of KS-like lesions in a mouse model. This indicates that vFLIP is a promising target for the treatment of the diseases caused by KSHV. vFLIP can activate the NF-KB and AP-1 signaling pathways, and is expressed during latent viral infection. Inhibition of vFLIP results in suppression of the constitutive NF-KB activity, downregulation of a specific set of antiapoptotic proteins and apoptosis of KSHV-infected cells. We have found that vFLIP directly interacts with TRAF2 through a specific TRAF-interacting motif, and that this interaction is essential for signaling by vFLIP. Therefore, our aim is to disrupt this interaction as a novel approach for the treatment of KSHV-associated diseases. Since protein-protein interactions have proven largely intractable to modulation using traditional "drug-like" molecules, we propose to achieve this by synthesizing and screening libraries of natural product-like molecules. Specifically, we will use polyketide libraries since this class of compounds has a demonstrated ability to modulate protein-protein interactions through peptidomimicry and is structurally distinct from typical drug-like molecules. We will synthesize both a parent library and biased libraries that are specifically designed to target the vFLIP/TRAF2 interaction. Screening will be done using a cell-based luciferase reporter assay, as well as a recombinant protein homogeneous time-resolved fluorescence (HTRF) assay. Our long-term goal is to identify potential therapeutic lead compounds that will be tested in murine models of KSHV-associated diseases followed by further preclinical development and eventually clinical trials. [unreadable] [unreadable] [unreadable]
|
1 |
2007 — 2008 |
Cesarman, Ethel |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Immunology Research Training Program @ Weill Medical College of Cornell Univ
DESCRIPTION (provided by applicant): The Immunology Research Training Program of the Weill Graduate School of Medical Sciences of Cornell University takes advantage of the breadth and depth of basic and clinical research talent among the component institutions (Weill Medical College [WMC], Sloan Kettering Institute [SKI], and Hospital for Special Surgery [HSS]) to provide a unique environment in which we strive to train the next generation of leaders in immunology. Graduate students and postdoctoral fellows are exposed to cutting edge immunology research ranging from basic structural biology and X-ray crystallography studies to clinical trials of immunotherapies that grew out of basic research in Immunology Program laboratories. The original T32 application stated that each component institution had a particular expertise to lend to the training: Inflammation and infectious disease (WMC), tumor immunology (SKI), and autoimmunity (HSS). While these continue to be strengths represented by those institutions, the Program has been so successful and interactions among the faculty so extensive, that there is now substantial overlap in the expertise at each institution (See Faculty Research Interests). The result has been to foster further tri-institutional interactions and collaborations. Most of the educational activities of the predoctoral and postdoctoral training segments of this Program have been combined, with the result that the experience is richer for both groups. Graduate students as well as fellows actively participate in Research-in-Progress seminars, the Immunology Retreat, Advanced Topics in Immunology courses, and external speaker seminars. Feedback from trainees is actively sought to change and improve the training program. This ensures that the trainees leave well-equipped to take their places as future leaders in the field. The graduate program leading to a Ph.D. degree is open to students who hold a Bachelor's degree from an accredited institution who want to enter biomedical research, as well as to individuals who already hold an advanced degree (e.g. M.D., D.V.M.) and wish to train for an independent academic research career in Immunology. Acceptance into the Program is based on college GPA and GRE scores, research experience, letters of recommendation, and personal interview. Predoctoral students are required to take a core curriculum in Immunology and related biomedical sciences and pass a rigorous Admissions exam prior to joining a thesis lab. Graduate studies generally take six years to complete. Applicants to the postdoctoral program must hold a Ph.D. or equivalent doctoral degree from an accredited institution. Acceptance is based upon past research and educational experience, as well as letters of recommendation. Postdoctoral fellowships average three years in duration. We have special programs in place to recruit underrepresented minorities to our Program. We realize the importance of having women and members of these minority groups among the future leaders of science.
|
1 |
2008 — 2010 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Survival Signals in Aids Lymphomas @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): Approximately half of AIDS related lymphomas are associated with infection by gamma herpesviruses. Most commonly, Epstein-Barr virus (EBV) is found in the lymphoma cells. A small proportion of AIDS-related lymphomas (approximately 5%) contain the Kaposi's sarcoma herpesvirus (KSHV), frequently in addition to EBV. KSHV-positive lymphomas usually present as primary effusion lymphomas (PEL), although solid variants exist. While rare, PELs have been very useful to study the role of KSHV in malignancies. Study of survival signals in PEL has led us to the identification of the transcription factor NF-kB as a critical signaling pathway, and of vFLIP as the gene encoded by KSHV that elicits NF-kB activation in latently infected PEL cells. vFLIP signaling to NF-kB is necessary for tumor cell survival. With respect to the more common EBV-associated lymphomas, NF-kB is also a critical cellular survival signal;the EBV-encoded proteins LMP1 and LMP2A are the critical viral survival signals in some of these tumors. Our broad hypothesis is that viral proteins provide survival signals, and that interference with these signals can be used as a pathogen-specific therapeutic approach for viral malignancies. Our goal is to better understand EBV-associated lymphomas by performing a comprehensive analysis to dissect the viral signals that are critical for tumor cell survival, in order to use a rational combinatorial approach for the treatment of AIDS lymphomas. This will be done through the following specific aims: 1) Characterize the mechanistic basis for the critical role of LMP2A in the setting of EBV-related lymphomas;2) Evaluate EBV gene and microRNA expression in EBV+ AIDS-related lymphomas;3) Determine which EBV-encoded gene products provide survival signals in EBV-associated lymphomas. This work will reveal which viral gene products are involved in EBV lymphomagenesis and will help select viral targets for selection of appropriate owth of lymphoma cells. Our data will help elucidate how best to inhibit EBV to improve the treatment of AIDS patients with lymphoma.
|
1 |
2010 — 2014 |
Cesarman, Ethel |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Immunology and Microbial Pathogenesis Research Training Program @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): The Immunology and Microbial Pathogenesis Research Training Program of the Weill Cornell Graduate School of Medical Sciences takes advantage of the breadth and depth of basic and clinical research talent among the component institutions (Weill Cornell Medical College [WCMC], Sloan Kettering Institute [SKI], and Hospital for Special Surgery [HSS]) to provide a unique environment in which we strive to train the next generation of leaders in immunology and microbial pathobiology. Graduate students and postdoctoral fellows are exposed to cutting edge immunology and infectious disease research ranging from basic structural biology and X-ray crystallography studies to clinical trials of immunotherapies that grew out of basic research in Immunology and Microbial Pathogenesis (IMP) Program laboratories. Each component institution has particular strengths to lend to the training: Inflammation and infectious disease (WMC), tumor immunology (SKI), and autoimmunity (HSS). However, the Program has been so successful in fostering tri- institutional interactions and collaborations among the faculty and trainees, that there is substantial overlap in the expertise at each institution. The result has been to foster tri-institutional interactions and collaborations. Most of the educational activities of the predoctoral and postdoctoral training segments of this Program are combined, resulting in a rich training experience for both groups. Graduate students as well as fellows actively participate in Research-in-Progress seminars, the IMP Retreat, Advanced Topics in Immunology courses, and external speaker seminars. Feedback from trainees is actively sought to change and improve the training program. The graduate program leading to a Ph.D. degree is open to students who hold a Bachelor's degree from an accredited institution, as well as to individuals who already hold an advanced degree and wish to train for an independent academic research career in IMP. Acceptance into the Program is based on college GPA and GRE scores, research experience, letters of recommendation, and a personal interview. We have special programs in place to recruit underrepresented minorities. Students are required to take a core curriculum in Immunology and related biomedical sciences and pass a rigorous Admission to Candidacy exam prior to joining a thesis lab. Graduate studies generally take six years to complete. Our IMP Program has been growing, with increased numbers of highly qualified students, so we project expanding this training program from 4 to 6 predoctoral trainees. RELEVANCE (See instructions): Health is virtually impossible without a competent immune system. In addition to the obvious infectious consequences of impaired immunity, dysregulation of immune control can lead to diseases as diverse as atherosclerosis, diabetes and cancer. In turn, these diseases also have immunologic consequences. The diverse expertise of our faculty provides trainees with a deep understanding of the basic mechanisms of this interplay and leaves them well-equipped to take their places as future leaders in the field.
|
0.976 |
2011 — 2015 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting Vflip For the Treatment of Kshv-Associated Malignancies @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is the most frequent cancer in HIV-infected individuals and the most common malignancy in several countries in subequatorial Africa. KS is largely incurable with current therapeutic options, and while KS is caused by the Kaposi's sarcoma herpesvirus (KSHV), no effective virus-specific therapies exist. KSHV also causes primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), which are also lethal and incurable diseases. Our overarching goal is to develop novel targeted therapies for KSHV-associate diseases. Experimental evidence indicates that the KSHV-encoded protein vFLIP is a potential therapeutic target. vFLIP is responsible for NF-kB activity in PEL cells, and elimination of vFLIP in these cells results in tumor cell apoptosis and autophagy. Transgenic expression of vFLIP in B cells induces tumors of B cell origin in mice. These observations support the role of vFLIP as a viral oncogene, and indicate that there is addiction to this viral protein in PEL cells, supporting the notion that inhibition of vFLIP is a viable therapeutic approach for the treatment of PEL. There is also substantial evidence that vFLIP plays a role in the pathogenesis of Kaposi's sarcoma, as it is expressed in lesional cells and has a variety of transforming effects when expressed in endothelial cells. Identification of inhibitors of KSHV vFLIP will be facilitated by the development of improved screening methodologies, adequate animal models and a deeper understanding of vFLIP-mediated oncogenesis. We have made progress towards these goals by identifying small molecule inhibitors of vFLIP, and developing vFLIP conditional knock-in mice with a robust tumor phenotype. We propose to perform additional preclinical studies to develop and test vFLIP inhibitors through the following specific aims: 1) characterize small molecule inhibitors of vFLIP already identified, perform structure-activity relationship analysis, and identify improved next generation inhibitors of vFLIP; 2) evaluate other vFLIP interactions and assess their relevance to vFLIP function and viral pathogenesis; and 3) test the most promising inhibitors of vFLIP in animal models of KSHV vFLIP malignancy. Through these aims we expect to identify robust vFLIP inhibitors and acquire the preclinical information necessary to pursue subsequent development for clinical testing of the best candidate. In addition, we expect to gain further insights on vFLIP structure and function, develop improved animal models, thereby advancing our understanding of the pathobiology of KSHV-associated malignancies.
|
0.976 |
2012 — 2016 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Kshv Latency in Vivo @ Weill Medical Coll of Cornell Univ
DESCRIPTION (provided by applicant): Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma (KS) and two lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The risk for KS is greatly increased in HIV-infected individuals and this is the most common malignancy in several countries in subequatorial Africa. KS is largely incurable with current therapeutic options. While KS is caused by KSHV, no effective virus-specific therapies exist. A better understanding of the pathobiology of KSHV infection, and robust animal models are essential for developing preventive and therapeutic strategies. Current animal models rely on expression of single viral genes in broad cellular populations, use of related animal viruses (none of which lead to KS or PEL-like disease), xenografts consisting of human tumor cells injected into immunodeficient mice, infection of humanized mice (with no resulting pathology), or implantation of cells previously infected or transfected in vitro. All of these animal models have significant limitation. Therefore, the goal of this project is to generate better mouse models to evaluate the effect of KSHV latent viral genes in vivo when selectively expressed in the specific cellular compartments that comprise the tumor cells in PEL and KS, namely B cells and endothelial cells. The majority of the cells in KSHV-associated tumors express only a few latent viral genes, although a very small and variable number of cells may also express some lytic genes. Conditional knock-in mice expressing the latent viral gene vFLIP in two different B cell subsets, all CD19+ cells or germinal center B cells, develop lymphadenopathies with features of MCD and tumors of B cell origin with long latency. We propose to extend these studies through the following specific aims: 1) discover complementing cellular and viral genetic events in vFLIP-mediated lymphomagenesis; 2) develop and characterize mice expressing inducible vFLIP in endothelial cells; and 3) determine the effect of expression of the entire KSHV latency locus in endothelial cells, and assess the contribution of vGPCR expression in rare scattered cells. Through these aims, we anticipate developing mouse models that resemble human disease, which will be useful for a deeper understanding of the mechanisms of KSHV pathogenesis, and testing novel therapeutic approaches.
|
0.976 |
2017 — 2018 |
Cesarman, Ethel Phipps, Warren |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Defining the Cellular Oncogenome of Kaposi Sarcoma @ Weill Medical Coll of Cornell Univ
Project Summary/Abstract KS is considered an AIDS-defining malignancy; however, there is still debate about whether KS is a reactive process or a true clonal cancer. Several features of KS suggest that it may not result from a transformation event that results in autonomously growing tumor cells, but represents a reactive process due to the combined effects of a virus with angiogenic properties and local or systemic inflammation. However, KS is very heterogeneous in terms of its histological, epidemiological and clinical features, and mounting evidence suggests that there may be different subtypes. KS is consistently associated with Kaposi sarcoma-associated herpesvirus (KSHV) infection, and this virus is now well documented to be the etiologic agent of KS. Therefore, a large number of studies have focused on understanding KSHV and the viral mechanisms of pathogenesis. Yet, there is a dearth of information about any cellular genomic alterations occurring in KS. These cellular genomic alterations characterize most other cancers, including those associated with infection by other human oncogenic viruses. Our preliminary sequencing studies on KS tumors have identified recurrent genomic losses of a tumor suppressor gene, WT1 as well as mutations in two proteins of the anaphase promoting complex (APC/C), involved in important cellular functions and cancer development. Moreover, our data suggest that some of these genetic alterations are clonal in some KS tumors. Building on these observations, we now propose to perform the first comprehensive analysis of cellular genetic alterations in KS on a large sample of clinically-annotated tumors. We will use state-of-the-art deep sequencing approaches to determine whether cellular genetic alterations exist in KS tumors, which genes are most commonly affected, and whether these mutations are monoclonal in some or all cases. We will also explore the relationship of mutational burden, specific gene mutations and clonality with KS clinical presentation and response to therapy. Through this approach, we will test the hypothesis that some KS lesions are polyclonal reactive processes largely driven by KSHV, and others full-blown malignancies with clonal genetic alterations in biologically relevant genes. We will test this hypothesis through two specific aims: 1) To determine whether all or a subset of KS tumors have recurrent genetic alterations in known cancer-related genes or other regions of the coding cellular genome; and 2) To characterize the relationship between tumor genomic alterations and KS clinical presentation and outcomes. By determining whether KS tumors possess genetic mutations within clonal cell populations, this study will contribute significantly to our basic understanding of disease pathogenesis, and could ultimately have important implications for disease staging and treatment.
|
0.976 |
2019 — 2021 |
Allis, Charles David Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Novel Onco-Histone Mutations in B-Cell Maligcies @ Weill Medical Coll of Cornell Univ
The genetic information encoded in DNA is packaged and interpreted by the cellular machinery within the context of chromatin. As the genome sequence remains largely unchanged throughout development, chromatin modifications represent a critical interface between the genome and regulatory inputs. Histone proteins are major constituents of chromatin; four core histone types make up the nucleosome particle, the basic unit of chromatin. The fifth type, linker histone H1, binds the nucleosome and the linker DNA between. Whereas the progress in understanding the function of core histones is significant in recent years, much of the linker histone H1 biology remains unknown. Mutations in linker histone H1 have been recently reported in approximately 30% of follicular lymphomas and diffuse large B cell lymphomas, and we have identified H1 mutations in 85% of Hodgkin's lymphomas of the nodular sclerosis subtype. Based on preliminary data, we hypothesize that H1 stem restricted dependency clones. B occurring causing cooperates overarching immune this control to tumor isoform loss of function induces lymphomagenesis by ectopically inducing an embryonic cell (ESC) gene expression signature that imparts unlimited self-renewal in GC B-cells that are otherwise in their ability to proliferate. We propose that ESC gene expression frees B-cells from their on T-cell help to survive and divide, resulting in expansion of aberrant pre-neoplastic B-cells Mechanistically, we propose that H1 is involved in PRC2 recruitment and chromatin compaction during cell differentiation, thereby repressing ESC genes. Thus, loss of function of H1 through somatic mutations in germinal center B cells results in reduction and redistribution PRC2 and H3K27 methylation chromatin decompaction and expression of ESC genes. Finally, we predict that H1 loss of function with lymphoma oncogenes such as BCL2 to induce malignant transformation. The goa of the proposed research is to reveal the contributions of linker histones to the humoral response and lymphomagenesis from both biochemical and biological perspectives. We will achieve through the following specific aims: 1) Determine the role and mechanism through which H1 is required to the GC reaction; 2) Determine the mechanism through which H1 mutations reprogram the epigenome drive lymphomagenesis; and 3) Determine whether and how H1 soforms function as bona fide lymphoma suppressors. The study of H1 is quite challenging, but we are uniquely poised to unravel GC canonical l i the molecular details and functional consequences of H1mutations in lymphoid carcinogenesis by bringing together leaders in the field of transcriptional regulation, chromatin, epigenetic regulation and lymphomagenesis.
|
0.976 |
2019 |
Cesarman, Ethel |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
The 22nd International Conference On Kaposi's Sarcoma-Associated Herpesvirus and Related Agents @ Weill Medical Coll of Cornell Univ
ABSTRACT This conference grant application requests funds to help support the 22nd International Conference on Kaposi's Sarcoma Herpesvirus and Related Agents in 2019. Our annual conference will bring together researchers and clinicians working on the oncogenic human herpesvirus, Kaposi's sarcoma herpesvirus (KSHV), and other closely related pathogens. The funds will be used to reduce the conference registration costs for outstanding US pre- and post- doctoral trainees, historically under-represented minorities, and scientists from poor countries who study oncogenic DNA viruses. The goals of these meetings are consistent with the mission statements of the NIH, NCI, NIAID, and NIDCR, namely, to advance and promote the pace of research on infections associated with human cancer and other diseases, including in the setting of HIV-AIDS. The KSHV conference will be held in New York City and will occur from the evening of June 30 through the morning of July 3, 2019. All remaining costs for these conferences will be raised from registration fees paid by the conferees and contributions from host institutions, foundations, and pharmaceutical and biotechnology companies. The main focus of the KSHV meeting is the biology of oncogenic herpesviruses and associated human diseases, with specific emphasis on viral pathogenesis, viral latency and reactivation, viral gene expression and replication, host responses to infection, epidemiology, vaccine development, and therapeutic intervention. In addition to KSHV, studies related to herpesvirus saimiri (HVS), murine herpesvirus-68 (MHV-68), and rhesus rhadinovirus (RRV) will be presented. The 22nd International Conference on Kaposi's Sarcoma-Associated Herpesvirus and Related Agents is the 25th anniversary of the virus's discovery. ! !
|
0.976 |
2020 — 2021 |
Cesarman, Ethel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
(Pq 6) New Models of Kshv Oncogenesis and Ks Immune Environment @ Weill Medical Coll of Cornell Univ
PROJECT SUMMARY Kaposi's common (KSHV, Castleman's KSHV-associated cells related of numerous been superficially ex will sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. diseases are difficult to model because this virus is species-specific, it does not transform in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been and incompletely described. The overarching goal is this application is develop preclinical in vitro, vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we applyobservations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine of engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use. major immune subsets in mice; the tumor immune environment in KS lesions in patients and test the role and 3)
|
0.976 |
2020 — 2021 |
Cesarman, Ethel Lambert, William Marcus |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Weill Cornell Initiative For Maximizing Student Development @ Weill Medical Coll of Cornell Univ
Project Summary/Abstract The Weill Cornell Graduate School (WCGS)?an educational and training partnership between Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center?is a premier institution for PhD training in the biomedical sciences. We look to leverage our training capacity ($275 million in research funding, 340 graduate school faculty, and over 330 PhD students) to increase our rates of attracting, retaining, and developing underrepresented minority (URM) doctoral students as leaders in the biomedical workforce. To accomplish this goal, we propose a Weill Cornell IMSD program with the following aims: (1) Attract a pool of well-prepared URM students to WCGS through partnerships with local and minority-serving institutions; (2) Build a robust, self-renewing community of URM doctoral students and faculty through an early start program, multifaceted mentorship, and social gatherings; and (3) Equip IMSD scholars with leadership training, professional skills and networks to be leaders in a variety of biomedical and science-related careers. WCGS is primed for training the next generation of URM biomedical scientists and we are confident that through the Weill Cornell IMSD, we can develop a steady stream of well-trained PhD's that will both diversify and bring innovation to the biomedical workforce.
|
0.976 |
2021 |
Cesarman, Ethel Nixon, Douglas F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulatory Crosstalk Between Human Endogenous Retroviruses, Hiv, and Ebv, in Lymphoma @ Weill Medical Coll of Cornell Univ
PROJECT SUMMARY/ABSTRACT Approximately 8% of the human genome is composed of sequences directly derived from germline infections of diverse retroviruses, which have accumulated over the past ~100 million years of mammalian evolution. None of these human endogenous retroviruses (HERVs) are known to represent fully functional retroviruses, but most have retained noncoding regulatory sequences that can control expression of cellular genes acting as promoters or enhancers, and some still encode proteins with various functional activities. While HERV sequences are often ignored as merely inconsequential ?junk? DNA, there is evidence that a subset of these elements play crucial roles in human physiology and disease, including cancer. Our previous work, as well as that of others, have shown that both HIV and EBV infections activate certain HERV families that have oncogenic activities, and our preliminary data reveal an overlap between these elements. Given that diffuse large B cell lymphomas (DBCL) are frequently associated with EBV infection in people living with HIV, we hypothesize that there is a complex intercellular regulatory crosstalk between AIDS related (AR)-DLBCL, HIV-infected T cells and the tissue microenvironment, that is in part mediated by a specific subset of HERVs and their derived products that are synergistically activated and promote oncogenesis. We will study DLBCL obtained from patients with or without EBV (and with or without HIV) from the USA and Brazil, which will be comprehensively characterized pathologically and molecularly using single-cell genomics and spatial transcriptomics. We will analyze these data using computational tools we have tailored to profile and link HERV and gene expression. Furthermore, we will establish in vitro models to dissect with precision the functional impact of HERV on the crosstalk between T cells infected by HIV and B cells with or without EBV. We will also determine if differential HERV expression creates neoantigenic epitopes, a feature that can be exploited for immunotherapy. This will be accomplished through three specific aims: 1) Characterize and profile HERV regulation and expression within single cells in DLBCL and AR-DLBCL; 2) Establish in vitro models to dissect the interaction between cellular and endogenous and exogenous viruses in AR-DLBCL; 3) Identification of neo-antigenic HERV epitopes in DLBCL and ascertain if cloned HERV specific CTL can lyse lymphoma cells in vitro. Our team consists of specialists in lymphoma biology and medicine, transposable elements and HERVs, HIV and EBV viral immunology. Together, we will generate understandings of how HERVs contribute to the pathogenesis of AR-DLCBL, and identify new antigenic targets for novel therapies.
|
0.976 |