MECHANISMS OF KSHV-INDUCED CELLULAR TRANSFORMATION

KSHV 诱导的细胞转化机制

• 批准号: 8173190
• 负责人: ASHLEE V. MOSES
• 金额: $ 15.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173190
• 关键词: Automobile Driving; Blood; Blood Vessels; CXCR4 gene; Cells; Commit; Computer Retrieval of Information on Scientific Projects Database; Data; Dermal; Development; Endothelial Cells; Funding; Gene Silencing; Genes; Goals; Grant; Human Herpesvirus 8; Imatinib mesylate; Immunocompetent; In Vitro; Individual; Institution; Kaposi Sarcoma; Lymphatic; Microarray Analysis; Organ; Pathogenesis; Play; Proto-Oncogene Protein c-kit; Proto-Oncogenes; Research; Research Personnel; Resources; Role; Signal Pathway; Skin Neoplasms; Source; Spindle Endothelial Cell; Stem Cell Factor; Tyrosine Kinase Inhibitor; United States National Institutes of Health; Visceral; Work; base; chemokine receptor; in vitro Model; metaplastic cell transformation; progenitor; promoter; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Kaposi's sarcoma (KS) is a multi-focal angioproliferative tumor of the skin and visceral organs that, while rare in immunocompetent individuals, is the most frequent AIDS-associated. Human herpesvirus 8 (HHV8/KSHV), the etiologic agent of KS, infects endothelial cells (EC) and spindle cells (SC) and plays an active role in driving tumor development. The goal of this project is to characterize the mechanisms through which KSHV reprograms EC/SC and contributes to tumor formation. We have developed in vitro models based on KSHV-infected dermal microvascular EC, and more recently lineage-committed blood vascular (BEC), lymphatic (LEC) and progenitor (EPC) EC. Our original work in DMVEC used microarray analysis and gene silencing to identify and validate cellular genes that contribute to KS tumorigenesis. The proto-oncogene c-Kit was the first KSHV-induced host gene that we investigated, and this work was aided by the availability of the tyrosine kinase inhibitor Imatinib mesylate. Our in vitro studies show that c-Kit is induced in KSHV-infected cells by differential activation of the c-Kit promoter and that downstream signaling pathways are preferentially activated in infected cells by the c-Kit ligand, SCF, which is highly expressed in KS tumors. Current work is focused on elucidating the role of other KSHV-induced host genes in KS pathogenesis. These include the chemokine receptors CXCR7 and CXCR4, which are expressed in KS tumors. Our recent data suggest that these molecules play a role in the seeding and development of KS tumors. This data formed the basis of a competing renewal application for this project that has been funded.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 卡波西肉瘤 (KS) 是一种皮肤和内脏器官的多灶性血管增殖性肿瘤，虽然在免疫功能正常的个体中罕见，但却是最常见的与艾滋病相关的肿瘤。人类疱疹病毒 8 (HHV8/KSHV) 是 KS 的病原体，感染内皮细胞 (EC) 和梭形细胞 (SC)，并在驱动肿瘤发展中发挥积极作用。该项目的目标是描述 KSHV 重新编程 EC/SC 并促进肿瘤形成的机制。 我们开发了基于 KSHV 感染的真皮微血管 EC 的体外模型，最近还开发了谱系定向血管 (BEC)、淋巴管 (LEC) 和祖细胞 (EPC) EC。 我们在 DMVEC 中的最初工作使用微阵列分析和基因沉默来识别和验证有助于 KS 肿瘤发生的细胞基因。原癌基因 c-Kit 是我们研究的第一个 KSHV 诱导的宿主基因，这项工作得到了酪氨酸激酶抑制剂甲磺酸伊马替尼的帮助。我们的体外研究表明，c-Kit 在 KSHV 感染的细胞中通过 c-Kit 启动子的差异激活而被诱导，并且下游信号通路在受感染的细胞中优先被 c-Kit 配体 SCF 激活，SCF 在 KS 肿瘤中高表达。目前的工作重点是阐明其他 KSHV 诱导的宿主基因在 KS 发病机制中的作用。 其中包括趋化因子受体 CXCR7 和 CXCR4，它们在 KS 肿瘤中表达。 我们最近的数据表明这些分子在 KS 肿瘤的种植和发展中发挥作用。 这些数据构成了该项目已获得资助的竞争性更新申请的基础。