REGULATION OF ANGIOGENESIS BY HUMAN HERPESVIRUS 8

人疱疹病毒8 （HHV8）是最近发现的一种DNA病毒，具有致癌和血管生成特性。HHV8与卡波西肉瘤有因果关系，卡波西肉瘤是一种内皮细胞起源的肿瘤，原发性积液性淋巴瘤（PEL）是免疫抑制患者中一种罕见的B细胞淋巴瘤。感染hhv8的内皮细胞的生长与血管内皮生长因子（VEGF）和VEGF受体的表达增加相关。感染hhv8的肿瘤细胞还能分泌维持未感染内皮细胞增殖的因子。阐明HHV8基因影响内皮细胞生长的机制对于理解HHV8诱导的血管生成和恶性转化至关重要。阐明与hhv8感染内皮细胞增殖有关的途径可能有助于了解肿瘤相关血管生成的一般机制。我们的长期目标是获得内皮细胞基因调控的理解，这将允许在广泛的人类癌症中针对血管生成的分子预防和治疗策略的发展。因此，我们建议检验以下假设：1。HHV8蛋白激活内皮细胞增殖的重要基因。2. 参与原代细胞转化的HHV8基因直接或间接激活内皮细胞基因。为了验证这些假设，我们提出了以下具体目标的研究：1。确定两个卡波西肉瘤相关疱疹病毒反式激活基因（Rta和ORF57）在调控血管增殖中重要的内皮细胞基因中的作用。2. 建立一种靶向基因突变的重组HHV8的制备方法，以确定内皮细胞转化和增殖需要哪些HHV8基因。

Human herpesvirus 8 (HHV8) is a recently described DNA virus with demonstrated oncogenic and angiogenic properties. HHV8 is causally associated with Kaposi's sarcoma, a tumor of endothelial cell origin and primary effusion lymphoma (PEL), a rare B cell lymphoma in immunosuppressed patients. Growth of HHV8-infected endothelial cells is correlated with increased expression of vascular endothelial growth factors (VEGFs) and VEGF receptors. HHV8-infected tumor cells also secrete factors capable of sustaining the proliferation of uninfected endothelial cells in trans. Delineation of the mechanisms by which HHV8 genes affect endothelial cell growth is critical to an understanding of HHV8-induced angiogenesis and malignant transformation. Elucidation of the pathways involved in proliferation of HHV8-infected endothelial cells is likely to yield insights into general mechanisms of tumor associated angiogenesis. Our long-term goal is to gain an understanding of endothelial cell gene regulation that will allow the development of molecular prevention and treatment strategies aimed at angiogenesis in a broad range of human cancers. We therefore proposed to test the following hypotheses: 1. HHV8 proteins activate endothelial cell genes important for proliferation. 2. HHV8 genes that are involved in transformation of primary cells directly or indirectly activate endothelial cell genes. To test these hypotheses, we proposed studies with the following Specific Aims: 1. To determine the role of two Kaposi sarcoma-associated herpesvirus trans-activating genes (Rta and ORF57) in the regulation of endothelial cell genes important in vascular proliferation. 2. To develop a method of producing recombinant HHV8 with targeted gene mutations to determine which HHV8 genes are required for endothelial cell transformation and proliferation.