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。子项目及 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，KSHV诱导c-Kit通过c-Kit启动子的差异激活，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。伊马替尼治疗艾滋病KS患者的II期临床试验正在进行中。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。这些包括酶HO-1和趋化因子受体CXCR 7和CXCR 4。我们的数据表明，这些分子在KS肿瘤的播种和发展中发挥作用。

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.