内切蛋白酶Furin对巨噬细胞极化功能调控作用及其分子机制

Furin is a cellular endoprotease that could proteolytically activate large numbers of proprotein substrates by hydrolysis, and has an essential role in many physiological and pathological processes. The extraordinary expression of Furin would lead to immune response activation, and damage the homeostasis of immune system. Macrophages, as one of the important innate cells, play pivotal roles in controlling immune homeostasis, immunity, tolerance, and innate and adaptive immunity in response to microorganisms. Three populations of activated macrophage, each of which has a distinct physiology, had been described as follow: classically activated macrophages, wound-healing macrophages and regulatory macrophages. The roles of Furin in macrophages is still unknown. The cell-specific gene knockout mice and the technical of cell biology, molecular biology and genomics will be applied in this project. The inspection of macrophages deficient in Furin could provide necessary theoretical basis for the biological research and application of targeting Furin.

Furin作为一种细胞内切蛋白酶，具有多种重要生理作用。在免疫系统中，T细胞特异缺失Furin表达诱发自身免疫性疾病发生，而Furin对巨噬细胞功能的调控研究未见报道。本项目将在我们前期研究基础上，主要应用髓系细胞特异敲除Furin小鼠与多种疾病模型、巨噬细胞体外诱导体系、细胞免疫学、分子生物学、生化、蛋白组学等技术手段，确定Furin在巨噬细胞发育、内稳态及其M1/M2极化的调控作用与生理/病理意义，解析其作用靶分子及其调控分子机制。该研究将为Furin的免疫调节作用提供必要实验数据，有助于我们理解蛋白酶对天然免疫应答的调控作用。

Furin作为一种细胞内切蛋白酶，具有多种重要生理作用。T细胞特异缺失Furin表达诱发自身免疫性疾病发生，而Furin对巨噬细胞功能的调控研究未见报道。本项目主要应用免疫细胞特异敲除Furin小鼠与多种疾病模型研究Furin在巨噬细胞、中性粒细胞、T细胞的发育、极化及功能。通过研究发现髓系细胞缺失Furin后巨噬细胞分泌炎症因子能力降低、吞噬能力增强但不影响巨噬细胞极化；Furin对中性粒细胞分泌炎症因子及吞噬功能均无影响。Furin可以促进CD8+T细胞增殖从而内源性调控小肠中CD8+T细胞的比例及数量，髓系细胞缺失Furin的小鼠诱发关节炎的比例显著降低，但其对LPS的敏感性以及伤口愈合时间均无差异。该研究将为Furin的免疫调节作用提供必要实验数据。