MECHANISMS OF KSHV-INDUCED CELLULAR TRANSFORMATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 卡波西肉瘤（KS）是一种多灶性血管增生性肿瘤的皮肤和内脏器官，而罕见的免疫功能正常的个人，是最常见的艾滋病相关。人疱疹病毒8型（humanherpesvirus 8，HHV 8/KSHV）是KS的病原体，感染内皮细胞（endothelialcell，EC）和梭形细胞（spindlecell，SC），在KS的发生发展中起着积极的作用。该项目的目标是表征KSHV重编程EC/SC并促进肿瘤形成的机制。 我们已经开发了基于KSHV感染的真皮微血管EC的体外模型，以及最近的谱系定向血管（BEC）、淋巴（LEC）和祖细胞（EPC）EC。 我们在DMVEC中的原始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，在KSHV感染的细胞中，c-Kit通过c-Kit启动子的差异激活而被诱导，并且下游信号传导途径在感染的细胞中优先被c-Kit配体SCF激活，SCF在KS肿瘤中高度表达。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。 这些包括在KS肿瘤中表达的趋化因子受体CXCR 7和CXCR 4。 我们最近的数据表明，这些分子在KS肿瘤的播种和发展中发挥作用。 这些数据构成了该项目的竞争性续期申请的基础。

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.