APDS系由PIK3CD基因功能获得性突变(PIK3CD GOF)引起编码蛋白P110δ激酶持续激活的原发性免疫缺陷疾病。新近研究结果表明APDS患者中T细胞过度活化，但关于其活化机制尚不完全清楚。前期结果显示P110δ持续激活可能通过改变Tnaive细胞糖代谢方式，促进Tnaive细胞糖酵解水平，以驱动Tnaive过度活化为TEff。因此，本项目利用APDS患者样本、PIK3CD GOF小鼠模型，借助OT-I、OT-II和Rag2 KO等模式动物，在前期研究基础上，阐释P110δ激活对T细胞分化和功能的调节作用，剖析P110δ激活对T细胞各阶段糖代谢途径的影响；采用代谢途径选择性抑制剂，上、下调关键基因表达，体内外深入解析P110δ持续活化影响T细胞分化和功能异常的代谢调控机制，继而探索纠正异常的糖代谢途径是否能逆转T细胞分化和功能异常，为APDS及相关性疾病提供新的治疗策略。

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an autosomal dominant primary human immunodeficiency (PID) caused by heterozygous gain-of-function mutations in PIK3CD, which encodes the p110δ catalytic subunit of PI3K. While the activation of naïve T cells has been extensively studied in APDS patients, the mechanisms underlying the activation and differentiation of naïve T cells into effector T cells are not fully understood. T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. Activated T cells generate energy in large part by increasing their rate of glucose uptake and glycolysis. Our preliminary results suggested that hyperactivated P110δ might drastically drive naïve T cell differentiation into effector T cells in vivo and in vitro by altering the glucose metabolic pathway characterized by rapidly switch metabolic programs from aerobic oxidation via the TCA cycle to glycolysis. Based on our previous findings and other related reports, we will fully dissect the effects of increased P110δ activity on the differentiation and functions of peripheral T cell by utilizing the PBMC samples from APDS patients, the PIK3CD GOF mice models previously constructed with CRISPR/Cas9 and other animal models such as OT-I，OT-II，Rag2 KO. The roles of hyperactivated P110δ activity on the specific pathway of glucose metabolic program will be defined using targeted metabolomics analysis and other common metabolic strategies ex vivo, in vivo and in vitro. In addition, we will using adoptive transfer and bone marrow chimeric mice models, and samples from APDS, together with modern techniques of molecular and cellular biology to explore metabolic reprogramming mechanisms of hyperactivated P110δ in T cell differentiation and function. Furthermore, we will test whether targeting glycolysis and mitochondrial metabolism could reverse or even normalize impaired T cell fates and functions. This proposed study has the potential to shed new light on pathophysiology mechanisms of APDS and to identify novel therapeutic venue for APDS and similar immune disorders.