HGF/c-MET通路在HIV/KSHV相关原发性渗出性淋巴瘤致病性中的作用

KSHV阳性的原发性渗出性淋巴瘤（PEL）恶性程度极高，平均生存期仅6个月，主要见于免疫力低下的AIDS患者及器官移植病人。目前，临床上对PEL无特效治疗方案，常规联合化疗效果很不理想。因此，对PEL的致病机理进行深入的研究以发现新药物靶标具有重要意义。本研究拟在发现阻断HGF/c-MET通路可以诱导PEL肿瘤细胞凋亡的基础上，首先分析阻断HGF/c-MET功能对细胞凋亡、细胞周期、活性氧信号通路蛋白的影响，阐明其诱发细胞凋亡的分子机制；其次通过研究PEL细胞内表达KSHV病毒基因与HGF/c-MET相互作用明确何种病毒蛋白可以激活该通路活性以及阻断HGF/c-MET功能对病毒基因表达的影响；最后通过基因芯片技术分析阻断HGF/c-MET功能对PEL细胞基因表达谱的影响，发现HGF/c-MET通路调控的新基因及药靶潜能,为今后体内实验、临床试验及最终改善PEL临床治疗提供有价值的线索。

The oncogenic gamma-herpesvirus known as the Kaposi’s sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL), which is usually found in immunocompromised persons such as AIDS patients and organ transplant recipients. PEL represents a rapidly progressive malignancy with very poor prognosis even under conventional chemotherapy, therefore it requires to indenty new targets or develop novel therapeutic strategies. The current studies are designed to elucidate the complex mechanisms for inducing PEL apoptosis during HGF/c-MET inhibition, the interaction between KSHV-encoded proteins and HGF/c-MET, and characterize the regulatory network related to HGF/c-MET pathway in KSHV+ PEL cells using microarrays. We anticipate that this work will lead to innovative mechanistic insights for the role of HGF/c-MET in HIV-associated lymphoma pathogenesis, and provide the framework for development of HGF/c-MET-focused therapies and implementation of clinical trials in future.