Regulation of lymphangiogenesis by KSHV vIRF3

KSHV vIRF3 对淋巴管生成的调节

• 批准号: 10252172
• 负责人: Jae U Jung
• 金额: $ 12.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-05 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252172
• 关键词: Regulation; lymphangiogenesis; KSHV; vIRF3

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.

项目概要 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。一些 研究表明淋巴管生成途径直接参与 KSHV 恶性肿瘤。 因此，拟议的研究旨在调查 KSHV 如何调节 淋巴管生成途径，最终可用于设计靶向治疗策略 阻止 KSHV 诱发的恶性肿瘤。根据我们的发现，我们假设 KSHV vIRF3 潜在蛋白指导 HDAC5 血管生成因子诱导全局基因表达变化 病毒诱导的淋巴管生成的过度萌芽形成，这是潜在的目标 治疗策略。在本提案中，我们将研究 vIRF3 相互作用如何阻止 HDAC5 磷酸化诱导的核输出；为什么 vIRF3 功能仅在 LEC 中明显 但 BEC 中则不然； vIRF3 功能的丧失是否会影响培养物中 KSHV 的肿瘤发生。 该提案旨在增强我们对 KSHV 如何解除淋巴管生成的理解 途径，因此应该为阻断 KSHV 诱发的恶性肿瘤的治疗策略提供信息， 特别是口头KS。