机体免疫应答和稳态调控机制异常会导致自身免疫类疾病、慢性炎症和肿瘤的发生。申请人已对VHL-HIF信号通路在Treg细胞、ILC2细胞和巨噬细胞的分化以及免疫应答方面开展系列研究，发现其与免疫细胞葡萄糖代谢失常以及免疫失衡类炎症疾病密切相关。据此提出“VHL-HIF通路介导糖代谢在免疫应答中的细胞与分子机制”的关键科学问题。利用独特的条件性基因敲除小鼠、多种实验性小鼠炎症模型以及先进的药物筛选体系，围绕Treg细胞、ILC2细胞和肺泡巨噬细胞，本课题将深入研究VHL-HIF信号通路和相关糖酵解代谢途径调控局部免疫稳态，在炎症性及自身免疫性疾病中的相关机制和依赖于细胞代谢重编程的可能干预手段。所获得研究结果将为为自身免疫病和炎症性疾病中基于Treg细胞、ILC2细胞和巨噬细胞的治疗方案提供新的思路，为探索基于该通路的新型靶点药物奠定坚实的理论基础。

Dysregulation of the immune homeostasis could result in severe diseases such as autoimmunity, chronic inflammation and cancer. We have previously identified the VHL-HIF pathway as a critical checkpoint for regulatory T (Treg) cell function and stability. VHL deficiency in Treg cells leads to systemic autoimmune diseases and IFNg-producing pathogenic Treg cells with aberrant glucose metabolism. Meanwhile, we show that selective VHL deletion in type 2 innate lymphoid cells (ILC2) or macrophages results in altered glycolysis and diminished type 2 lung inflammation after papain challenge, indicating that the VHL-HIF pathway also plays important roles in regulating innate immune cells and allergic lung inflammation. Our convincing preliminary studies thus form a strong premise for us to tackle the underlying mechanisms, by using a combination of state-of-the-art molecular, cellular and pharmacological approaches, plus unique mouse models of conditional gene targeting and inflammation. The expected results will significantly advance our basic knowledge of the VHL-HIF-glycolysis axis in the regulation of immune responses and homeostasis, and at the same time, will provide insights into therapeutic intervention for the prevention and treatment of autoimmune and inflammation diseases in humans.