cGAS-STING信号转导通路的调控新机制及相关先导化合物研究

Recent breakthroughs on how hosts sense and respond to aberrant cytosolic DNAs have transformed the study of innate immunity. Understanding the cGAS-STING signaling pathway represents a new frontier of biomedicine. Via the patronage of the former NSFC grants, we have established the relevant research methods/platforms and published papers in high-impact journals. As the spin-off, we have successfully screened out several novel signaling proteins and TCM lead compounds, which are potentially essential for relaying or modulating the cGAS-STING signaling. Employing the HSV-1/Listeria monocytogenes-infectious- and TREX-/- autoimmune- models, we aim to address their critical biological functions at molecular, cellular and organismal levels; to explore how ubiquitination or NEEDylation regulates the cGAS-STING signaling spatially and temporally; to elucidate how TCM lead compounds specifically target and modulate this pathway. The expected insights will be beneficial to design and develop novel approaches to limiting infectious and autoimmune diseases and to boosting the immuno-cancer therapy.

识别与应答细胞质异源DNA的生物学研究获得突破性进展，探索cGAS-STING细胞信号转导通路的组成、功能、调控、干预成为生物医学的前沿领域之一。申请人在基金委已结题项目的资助下，建立了固有免疫信号转导的研究平台与体系，发表系统性的高影响力研究论文。通过大规模功能筛选的策略，鉴定到数个新的蛋白质和天然小分子化合物，具有调节cGAS-STING信号通路的潜在功能。本项目拟以病毒、细菌感染和自身免疫小鼠模型，从分子、细胞、动物模型等层面，研究相关蛋白质的新生物学功能;揭示蛋白质翻译后修饰动态调控cGAS-STING信号通路的分子细胞机制; 阐释天然小分子化合物调节该通路的位点与作用机理；为防治感染性、自身免疫性疾病和增强肿瘤免疫效果提供潜在的新靶点和新策略。

识别胞质DNA的cGAS-STING免疫通路在维持机体的免疫稳态中发挥关键作用。cGAS-STING通路功能的正常发挥对机体的抗感染至关重要，而该通路的调控失衡将导致自身免疫性疾病、慢性炎症等重大难治性疾病。针对这些疾病的药物研发极大的依赖于cGAS-STING通路分子调控机制的阐明和小分子化合物的研发。本项目的研究工作开展顺利，我们筛选并鉴定多个调控cGAS-STING信号通路的新蛋白质（Prmt5、CYLD、RNF111、UXT），并解析其生物学功能和分子作用机制；挖掘泛素及类泛素化（NEDD8、ISG15）修饰调控cGAS-STING信号通路的靶点蛋白和功能；开发了两种STING蛋白的小分子抑制剂AstinC和SN-011，并阐明其在调节固有免疫和干预自身免疫疾病中的作用。本项目的研究成果将为治疗cGAS-STING免疫通路的调控失衡导致的感染类和自身免疫性等多种疾病提供新靶点和新策略。