BIOLOGY OF KSHV/HHV8 G PROTEIN COUPLED RECEPTOR

KSHV/HHV8 G 蛋白偶联受体的生物学

• 批准号: 7908037
• 负责人: Enrique A Mesri
• 金额: $ 14.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908037
• 关键词: AIDS related cancer; Accreditation; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Automobile Driving; Biology; Cell Proliferation; Cell Survival; Cells; Clinical; Complex; Development; Endothelial Cells; Endothelium; Funding; G-Protein-Coupled Receptors; Gastrointestinal tract structure; Gene Expression; General Population; Genes; Genetic Suppression; Genetic Transcription; Genome; Growth; HIV; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Intervention; Kaposi Sarcoma; Knowledge; Lead; Lesion; Ligands; Lymphatic Endothelium; Lymphoid; Lymphoma; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Oncogenic; Oncornaviruses; Pathogenesis; Pathogenicity; Pattern; Pharmaceutical Preparations; Phenotype; Play; Premalignant; Research Personnel; Risk; Role; Signal Transduction; Skin; Small Interfering RNA; Spindle Endothelial Cell; Staging; Surrogate Markers; Targeted Research; Testing; Therapeutic Studies; Toxic effect; Up-Regulation; Vascular Endothelial Growth Factors; Viral; Viral Genes; Viral Pathogenesis; Work; Yang; angiogenesis; autocrine; celecoxib; cell growth; cell immortalization; cell transformation; chemokine; cyclooxygenase 2; effusion; gamma-2 herpesvirus; in vivo; in vivo Model; insight; lymph nodes; lytic replication; mortality; mutant; neoplastic; null mutation; paracrine; podoplanin; pre-clinical; programs; receptor; response; theories; therapeutic target; tool; tumorigenesis

DESCRIPTION (provided by applicant): This proposal is directed to investigate the role in KS pathogenesis and KSHV biology of the viral G protein coupled receptor encoded by ORF74 of KSHV (vGPCR). vGPCR appear to be a critical gene in KSHV pathobiology because it can trigger important signaling cascades and induce cellular responses that recapitulate the KS-phenotype in vitro and in vivo. These include activation of VEGF mediated angiogenicity and tumorigenesis. The tools and knowledge generated by the present application in addition to recent advances in the KSHV field provide the necessary armamentarium to undertake a definitive study in vGPCR pathobiology and assess its validity as therapeutic target. Our working hypothesis is that vGPCR expression during lytic replication has the capacity to regulate and host viral gene expression leading to increased endothelial cell survival during and paracrine angiogenic stimulation. That these activities that are directed to enhance viral replication and infection are pre-neoplastic and pro-angiogenic in EC, and thus vGPCR expression in EC can promote KS-cell and vessel growth and also lead to oncogenic transformation. To study the functional role of vGPCR in KSHV infection and pathogenesis we will modulate vGPCR expression during KSHV infection by activation with the chemokine Gro-a and by vGPCR-null mutations. To study the role of KSHV in infection and replication we will 1-Determine at the cellular and molecular level how vGPCR-modulation affects the ability of KSHV to infect and replicate in 293 and endothelial cells. 2- Study how vGPCR expression affects cell survival, survival signaling and KSHV gene transcription during KSHV infection. To determine the role of vGPCR in KSHV mediated Kaposi's sarcoma pathogenesis we will study 1- The contribution of vGPCR to paracrine activation of angiogenesis by KSHV infection using "in vitro" and "in vivo" models. 2- The contribution of vGPCR to the recapitulation of KS-like phenotypes in KSHV infected endothelial cells. 3- The participation of vGPCR in primary endothelial cell immortalization, transformation and angiogenic activation. In addition to test the validity of vGPCR as target for AIDS-KS therapy, this research will provide models that identify vGPCR pathogenic responses in the context of KSHV infection and identify approaches targeted to vGPCR function that are able to block KSHV pathogenesis.

描述（由申请人提供）：本提案旨在研究由 KSHV 的 ORF74（vGPCR）编码的病毒 G 蛋白偶联受体在 KS 发病机制和 KSHV 生物学中的作用。 vGPCR 似乎是 KSHV 病理学中的关键基因，因为它可以触发重要的信号级联并诱导细胞反应，从而在体外和体内重现 KS 表型。这些包括激活 VEGF 介导的血管生成和肿瘤发生。除了KSHV领域的最新进展之外，本申请产生的工具和知识提供了必要的设备来进行vGPCR病理学的明确研究并评估其作为治疗靶点的有效性。我们的工作假设是，裂解复制期间的 vGPCR 表达具有调节和宿主病毒基因表达的能力，导致在旁分泌血管生成刺激期间增加内皮细胞存活率。这些旨在增强病毒复制和感染的活性在 EC 中是肿瘤前和促血管生成的，因此 EC 中 vGPCR 的表达可以促进 KS 细胞和血管生长，并导致致癌转化。为了研究 vGPCR 在 KSHV 感染和发病机制中的功能作用，我们将通过趋化因子 Gro-a 激活和 vGPCR 无效突变来调节 KSHV 感染期间 vGPCR 的表达。为了研究 KSHV 在感染和复制中的作用，我们将 1-在细胞和分子水平上确定 vGPCR 调节如何影响 KSHV 在 293 细胞和内皮细胞中感染和复制的能力。 2- 研究 KSHV 感染期间 vGPCR 表达如何影响细胞存活、存活信号传导和 KSHV 基因转录。为了确定 vGPCR 在 KSHV 介导的卡波西肉瘤发病机制中的作用，我们将使用“体外”和“体内”模型研究 1- vGPCR 对 KSHV 感染引起的血管生成的旁分泌激活的贡献。图2-vGPCR对KSHV感染的内皮细胞中KS样表型的再现的贡献。 3- vGPCR参与原代内皮细胞永生化、转化和血管生成激活。除了测试 vGPCR 作为 AIDS-KS 治疗靶标的有效性外，该研究还将提供模型来识别 KSHV 感染情况下的 vGPCR 致病反应，并确定能够阻断 KSHV 发病机制的针对 vGPCR 功能的方法。