MECHANISMS OF KSHV-INDUCED CELLULAR TRANSFORMATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 卡波西氏肉瘤(KS)是一种皮肤和内脏器官的多灶性血管增生性肿瘤，虽然在免疫功能正常的人中很少见，但却是最常见的与艾滋病相关的肿瘤。人类疱疹病毒8型(HHV8/KSHV)是KS的病原体，感染内皮细胞(EC)和梭形细胞(SC)，在肿瘤的发生发展中起着积极的作用。这个项目的目标是描述KSHV重新编程EC/SC并促进肿瘤形成的机制。我们已经建立了基于KSHV感染的皮肤微血管内皮细胞的体外模型，最近又建立了基于血统决定的血管(BEC)、淋巴管(LEC)和祖细胞(EPC)的EC。我们在DMVEC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，这项工作得益于酪氨酸激酶抑制剂甲磺酸伊马替尼的可用性。我们的体外研究表明，在KSHV感染的细胞中，c-Kit是通过c-Kit启动子的差异激活而诱导的，而在感染细胞中，下游的信号通路优先被在KS肿瘤中高表达的c-Kit配体SCF激活。伊马替尼治疗艾滋病-KS患者的第二阶段临床试验正在进行中。目前的工作集中在阐明KSHV诱导的其他宿主基因在KS发病中的作用。其中包括HO-1酶和趋化因子受体CXCR7和CXCR4。我们的数据表明，这些分子在KS肿瘤的种子和发展中发挥作用。

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 KSHVinfected 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. A phase II clinical trial of Imatinib therapy in AIDS-KS patients is in progress. Current work is focused on elucidating the role of other KSHV-induced host genes in KS pathogenesis. These include the enzyme HO-1 and the chemokine receptors CXCR7 and CXCR4. Our data suggest that these molecules play a role in the seeding and development of KS tumors.