肾透明细胞癌（ccRCC）是最为常见的泌尿系统恶性肿瘤之一，以显著的脂质代谢异常及广泛的缺氧诱导因子2α（Hypoxia induced factor 2α，HIF2α）激活作为特征。虽然两者均在ccRCC的发生发展中起重要作用，但有关两者之间的内在关系却鲜有系统性研究。申请者前期研究发现代谢高度相关的分子烟酰胺核苷酸转氢酶（NNT）可通过激活脂质棕色化反应来抑制ccRCC细胞的脂质堆积和癌化，还发现HIF2α可以显著抑制这一过程的发生。据此，申请者提出HIF2α通过抑制NNT介导的脂质棕色化反应促进ccRCC的进展及脂质堆积的假说。本项目拟利用细胞模型，动物模型及大量的临床标本，采取多种分子生物学手段探讨HIF2α的激活与NNT介导的脂质棕色化在ccRCC发生发展中的作用，进一步阐明其中的具体机制，从而为ccRCC临床诊断和治疗提供新的思路和靶点。

Clear cell renal cell carcinoma (ccRCC) is one of the most common lethal neoplasm in the urological system which is characterized by significant metabolic dysfunction and extensive HIF2α activation. Although emerging evidence has highlighted the important roles of these two hallmarks in the development and progression of ccRCC, the correlation between them lacks systematic research. Our preliminary study found that the metabolic-related gene Nicotinamide Nucleotide Transhydrogenase (NNT) can suppress ccRCC progression and lipid accumulation by promoting lipid browning. We also found that HIF2α can significantly inhibit this process. Accordingly, we hypothesize that HIF2α promotes cancer progression of ccRCC and lipid accumulation by inhibiting the NNT-activated lipid browning. This project intends to verify the significance of HIF2α and NNT-activated lipid browning in the development of ccRCC by using various molecular biological approaches to explore cell models, animal models and clinical specimen, and further clarify the specific mechanisms underneath, thereby provide a novel insight into the targets for the clinical diagnosis and treatment of ccRCC.