肾透明细胞癌（clear cell renal cell carcinoma, ccRCC）是最主要的肾癌类型，具有典型的代谢重编程特征，表现为Warburg效应、线粒体功能紊乱和脂肪酸积累。以往研究提示VHL突变或缺失导致HIF1α持续激活会造成ccRCC代谢重编程，但ccRCC代谢重编程的分子机制尚不清楚。我们前期结果显示GIT2在ccRCC癌组织中高表达，直接调控ccRCC的代谢重编程。本项目拟通过代谢组和代谢流分析、互作蛋白鉴定及小鼠实验，揭示GIT2在ccRCC代谢重编程中的功能和作用机制。研究目标包括：鉴定GIT2对ccRCC代谢网络的调控作用；验证GIT2抑制线粒体合成和功能，及对肿瘤耐药性的调控作用；阐明GIT2调控代谢重编程的分子机制；使用动物模型验证GIT2的功能。本课题的完成将阐明GIT2调控ccRCC代谢重编程的作用机制，并为ccRCC的治疗提供新思路。

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by typical metabolism reprogramming phenotypes of Warburg effect, mitochondria dysfunction and elevated fat deposition. Metabolic reprogramming enables cancer cells to rapidly proliferation under conditions of nutrient lack and hypoxia, and envade the immune system. ccRCC metabolic alterations are related with the mutation or depletion of VHL which can lead to the continuous activation of HIF1α, while 80% ccRCC patients have VHL mutation or depletion. However, the molecular mechanisms of metabolic reprogramming in ccRCC remains unclear. As our previous data shown, GIT2 is overexpressed in ccRCC tumor tissues, and related to metabolic reprogramming of ccRCC. The work proposed herein is to study the function and mechanism of GIT2 in metabolic reprogramming through metabolic flux analysis, identification of binding partners and mouse assay. The study is aimed to 1) identify that function of GIT2 in ccRCC metabolic reprogramming, 2) confirm if GIT2 knockdown could enhance mitochondrial functions and sensitize ccRCC cells to cytotoxic therapy, 3) illustrate the mechanism of GIT2 in metabolic reprogramming by finding the upstream and downstream regulators of GIT2, 4) verify the functions of GIT2 by using mouse model. The completion of this proposed work will shed light on systematic understanding of GIT2 functions in ccRCC metabolic reprogramming, and provide new insights into ccRCC therapy.