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Functional analysis of KSHV GPCR in human lymphocytes

人淋巴细胞中 KSHV GPCR 的功能分析

基本信息

批准号：
7286381
负责人：
MARK L CANNON
金额：
$ 12.53万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2008-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7286381
关键词：
Address Affect Animals Antibodies Apoptosis B-Lymphocytes Binding Sites Biological Assay Biology Cell Cycle Cell Line Cell Proliferation Cell Survival Cell physiology Cells Characteristics Conditioned Culture Media Cultured Cells Data Development Disease Dose Down-Regulation Doxycycline Endothelial Cells Fibroblast Growth Factor 2 Fibroblasts Flow Cytometry Functional disorder G-Protein-Coupled Receptors Genes Genetic Transcription HIV Infections Hematopoietic Homologous Gene Human Human Herpesvirus 8 Human herpesvirus 8 G protein-coupled receptor IL8 gene IL8RB gene Infection Interleukin 8A Receptor Interleukin-6 Kaposi Sarcoma Label Length Lesion Life Cycle Stages Lymphocyte Lymphocyte Biology Lymphoma Lytic Lytic Phase MAPK1 gene MAPK14 gene Measures Mediating Mediator of activation protein Medical Mentorship Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Mononuclear Multicentric Angiofollicular Lymphoid Hyperplasia Normal Cell Pathology Patients Phase Phenotype Phosphotransferases Physicians Plasmids Play Ploidies Production Propidium Diiodide Protein Overexpression Proteins Research Research Personnel Role Science Scientist Signal Pathway Signal Transduction Signaling Molecule Source Staining method Stains Standards of Weights and Measures Stimulus Stress Techniques Tetracycline Tetracyclines Thinking Thymidine Time Training Transcription Factor AP-1 Universities Vascular Endothelial Growth Factors Viral Viral Genes Virion Virus Work angiogenesis autocrine cell type chemokine chemokine receptor college cytokine design effusion in vivo inhibitor/antagonist lymphocyte proliferation medical schools novel novel strategies paracrine programs promoter protein expression receptor response sarcoma therapeutic target tool transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Kaposi?s sarcoma-associated herpesvirus (KSHV/HHV-8) is closely associated with Kaposi?s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman?s disease, disorders associated with HIV infection. KSHV encodes a G protein-coupled receptor (GPCR) most homologous to the human IL-8 receptors CXCR1 and CXCR2. Transcription of vGPCR has been shown in KS and PEL, and evidence in transfected animal cell lines suggests that KSHV GPCR may be involved in KSHVmediated angiogenesis and oncogenesis. vGPCR has not, however, been studied in the context of PEL cell lines or any other human cell of hematopoietic origin. Since signaling molecules behave differently in different cellular contexts, such work will be fundamental in understanding the role of vGPCR in KSHV-mediated disease. To this end, Dr. Cannon designed a novel single plasmid construct that permitted development of PEL cell lines that can be made to over-express vGPCR in a dose-dependent manner using tetracycline. Preliminary data in these cell lines already show that vGPCR has quite different downstream effects than in other cell lines. Namely, vGPCR causes activation of the mitogen-activated ERK2, downregulation of stress-related p38, and decreased cell viability. Furthermore, vGPCR upregulates NFkB and AP-1 activity, two transcription factors intimately involved in B cell physiology. Importantly, other KSHV genes have been shown to have AP-1 and NFkB-responsive promoters. These cell lines are ideal tools to study the following: 1) vGPCR signaling mechanisms and downstream effects on PEL cell proliferation, cell cycle and apoptosis, 2) vGPCR-mediated autocrine/paracrine effects including secretion of VEGF, bFGF, IL-6 and other cytokines known to play a role in angiogenesis and PEL/KS biology, 3) vGPCR-mediated effects on KSHV gene transcription and life cycle. Another major aim of the proposal is to provide didactic and research components in a phased manner to provide the applicant with effective training as a physician-scientist. Dr. Cannon will be studying at the Weill Medical College and School of Medical Sciences of Cornell University and working in the lab under the mentorship of Dr. Ethel Cesarman of the Department of Pathology.

描述（由申请人提供）：Kaposi？肉瘤相关疱疹病毒 (KSHV/HHV-8）与Kaposi？肉瘤（KS），原发性渗出性淋巴瘤（PEL）和多中心Castleman？s疾病，紊乱与HIV感染有关。KSHV编码G蛋白偶联受体 GPCR与人IL-8受体CXCR 1和CXCR 2最同源。 vGPCR的转录已在KS和PEL中显示，并且在KS和PEL中的证据显示vGPCR的转录。转染的动物细胞系表明KSHV GPCR可能参与KSHV介导的血管生成和肿瘤发生。然而，尚未研究vGPCR 在PEL细胞系或任何其他造血干细胞的情况下，起源由于信号分子在不同的细胞中表现不同，在这种背景下，这样的工作将是理解vGPCR在以下方面的作用的基础： KSHV介导的疾病。为此，坎农博士设计了一个新颖的单曲质粒构建体允许开发可使用四环素以剂量依赖性方式过量表达vGPCR。这些细胞系中的初步数据已经表明，vGPCR具有相当的与其他细胞系不同的下游效应。也就是说，vGPCR导致有丝分裂原活化的ERK 2的活化，应激相关的 p38，并降低细胞活力。此外，vGPCR上调NF κ B和NF κ B的表达。 B细胞中两种转录因子AP-1活性的研究 physiology.重要的是，其他KSHV基因已被证明具有AP-1和 NF κ B应答启动子。这些细胞系是研究 1）vGPCR信号转导机制及其下游对PEL细胞的影响增殖、细胞周期和凋亡，2）vGPCR介导的自分泌/旁分泌包括VEGF、bFGF、IL-6和其他已知的细胞因子的分泌，在血管生成和PEL/KS生物学中起作用，3）vGPCR介导的对 KSHV基因转录和生活史。该提案的另一个主要目的是分阶段提供教学和研究部分，申请人作为一个医生，科学家有效的培训。坎农医生会在威尔医学院和医学科学学院学习，康奈尔大学，并在Ethel博士的指导下在实验室工作病理科的塞萨曼