KSHV编码的vFLIP蛋白通过泛素降解宿主SAP18蛋白促进内皮细胞侵袭与血管生成及其分子机制的研究

卡波氏肉瘤病毒（KSHV）感染导致卡波氏肉瘤（KS）在AIDS患者中频繁发生（AIDS-KS）。AIDS-KS侵袭传播性强、预后差、死亡率高。尽管KSHV vFLIP能够活化NF-κB通路促进细胞存活、增殖与肿瘤形成，但其在细胞侵袭和血管生成中的作用及机制目前尚不清楚。课题组近期的预实验结果显示，vFLIP能够促进内皮细胞侵袭和血管生成，其中被泛素降解的宿主蛋白Sin3相关多肽P18（SAP18）可能发挥重要作用。本项目拟（1）鉴定SAP18是介导KSHV vFLIP促进内皮细胞侵袭和血管生成的关键蛋白；（2）阐明vFILP调控SAP18以及SAP18参与上述过程的分子机制；（3）运用遗传学技术反向证实关键蛋白SAP18、SAP18结合蛋白及下游基因参与调控vFLIP诱导内皮细胞侵袭和血管生成。本项目致力于阐明KSHV诱导恶性肿瘤KS的发病机制，为临床防治AIDS-KS提供潜在的药物靶点。

Kaposi's sarcoma-associated herpesvirus (KSHV) infection caused KS, a malignant tumor that frequently happens to AIDS patients (AIDS-KS). AIDS-KS is of high invasion and metastasis, poor prognosis and significant mortality. KSHV encoded oncogenic protein vFLIP has been shown to promote cell survival, proliferation and tumor formation by activating NF-κB signaling, however, its role in KSHV-induced tumor dissemination and angiogenesis, and its underlying mechanism remain unknown. Recent pre-experiment showed that vFLIP had a strong ability of inducing cell invasion and angiogenesis, and Sin3A associated protein 18 (SAP18) degraded by ubiquitin-proteasome pathway might be involved in the process. Thus, our expectations are to identify that SAP18 is involved in vFLIP-induced cell invasion and angiogenesis, to elucidate the molecular mechanisms of vFLIP regulated SAP18 and SAP18 regulated vFLIP-induced cell invasion and angiogenesis, and to further confirm that SAP18, its interactive protein and the downstream genes participate in vFLIP-induced cell invasion and angiogenesis using reverse genetics assay. Our research will contribute to clarify the pathogenesis of KS induced by KSHV and provide potential targets for clinical prevention and therapy of AIDS-KS.