Regulation of lymphangiogenesis by KSHV vIRF3

项目摘要 卡波西肉瘤相关疱疹病毒(KSHV)是卡波西肉瘤的病原体 (KS)：尤其是口腔KS是最常见的HIV相关肿瘤之一。一批 研究表明，淋巴管生成途径直接参与了KSHV的恶性转化。 因此，拟议的研究旨在调查KSHV如何监管 淋巴管生成途径，最终可能被用于设计有针对性的治疗策略 阻断KSHV诱导的恶性转化。根据我们的发现，我们假设KSHV vIRF3 潜伏蛋白指导HDAC5血管生成因子诱导全球基因表达变化 病毒诱导的淋巴管生成的超芽形成，这是一个潜在的靶点 治疗策略。在本提案中，我们将研究vIRF3交互如何阻止 磷酸化诱导HDAC5的核输出；为什么vIRF3功能只在晶状体上皮细胞中明显 但在BEC中不是；以及vIRF3功能的丧失是否会影响KSHV在培养中的致癌作用。 这项建议旨在加强我们对KSHV如何放松对淋巴管生成的监管的理解 途径，因此应该成为阻止KSHV诱导的恶性肿瘤的治疗策略， 特别是口服KS。

Project Summary Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS): especially, oral KS is one of the most common HIV-associated neoplasms. A number of studies have indicated that lymphangiogenic pathways are directly involved in KSHV malignancy. Thus, the proposed study is directed toward investigating how KSHV regulates the lymphangiogenic pathway, which may ultimately be used to design a targeted therapeutic strategy to block KSHV-induced malignancy. Based on our findings, we hypothesize that the KSHV vIRF3 latent protein directs HDAC5 angiogenic factor to induce the global gene expression change and hyper-sprouting formation for virus-induced lymphangiogenesis, which is a potential target for therapeutic strategy. In this proposal, we will study how the vIRF3 interaction blocks the phosphorylation-induced nuclear export of HDAC5; why vIRF3 functions are apparent only in LECs but not in BECs; and whether loss of the vIRF3 function affects KSHV oncogenesis in cultures. This proposal is targeted to enhance our understanding how KSHV deregulates lymphangiogenic pathway and thus should inform therapeutic strategies to block KSHV-induced malignancy, specifically oral KS.