Ufm1类泛素化 E3连接酶在肠道稳态中的作用和机制

Intestinal homeostasis plays a crucial role in maintaining microbiota homeostasis and normal functions of the gut. Disruption of this homeostasis would lead to inflammatory bowel disease (IBD) and even cancer. The incidence of IBD has been growing rapidly in china in recent years, and there is no curable treatment except surgery. Therefore, thorough elucidation of etiology and the underlying mechanism of pathogenesis would be the key for development of novel therapies. The Ufm1 conjugation system is a novel ubiquitin-like modification system, and the studies of its biological functions are emerging. Recently, we have successfully establish the knockout mouse models of Ufl1 and Ufbp1, two key components of a putative E3 ligase. Our published work demonstrates the indispensable of Ufl1 and Ufbp1 in embryogenesis and erythropoiesis. Furthermore, our preliminary study using IEC-specific knockout models of Ufl1f and Ufbp1 shows that Ufl1/Ufbp1 complex plays a pivotal role in maintaining intestinal homeostasis, especially the survival and function of Paneth cells. In this study, we will further elucidate the function and mechanism of Ufl1/Ufbp1-mediated regulation of intestinal homeostasis. Our study will provide insight on new candidate genes of IBD and new theoretical basis for development of novel therapies.

肠道稳态的维持对肠道菌群分布和正常功能起着及其重要的作用。而肠道稳态的失衡将引起肠道炎症(IBD)甚至肠癌。炎症性肠病发病率在中国近年内迅速增加。目前为止, 除了手术还没有完全治愈方法。因此, 阐明其致病原因和发病机制对发展新的治疗方法起到关键的作用。Ufm1类泛素化是一新的类泛素化修饰系统, 其生物学功能刚开始被认知。最近，我们首先成功建立了Ufm1 E3连接酶Ufl1和Ufbp1基因敲除小鼠。我们发表的工作表明Ufl1和Ufbp1在胚胎发育和红细胞生成过程中起着不可缺失的作用。而我们的前期工作也显示Ufl1和Ufbp1在维持肠道稳态，特别是在肠道Paneth细胞的成活和功能中起着十分重要的作用。在本课题中，我们将进一步阐明Ufl1和Ufbp1在维持肠道稳态以及调控肠道炎症作用和分子机制，为进一步探索这些肠病的发病机制提供新的候选基因和理论依据, 最终为治疗这些疾病开辟新途径。

肠道稳态的维持对肠道菌群分布和正常功能起着及其重要的作用。而肠道稳态的失衡将引 起肠道炎症(IBD)甚至肠癌。炎症性肠病发病率在中国近年内迅速增加。目前为止, 除了手术，还没有完全治愈方法。因此, 阐明其致病原因和发病机制对发展新的治疗方法起到关键的作用 。Ufm1类泛素化是一新的类泛素化修饰系统, 其生物学功能刚开始被认知。我们的结果表明Ufm1 E3链接酶Ufl1/Ufbp1在维持肠道稳态和肠道上皮细胞正常功能中起到不可缺失的作用。Ufm1类泛素化代表着一个全新的调控Paneth细胞的存活和功能的分子机制。同时 IEC特异性的Ufbp1/PERK和Ufbp1/IRE1双基因敲除模型小鼠模型建立了Ufm1类泛素化和UPR的关系。我们的结果对Ufm1类泛素化修饰系统的生物学功能及机理的研究起到极大的促进作用，为进一步探索炎症性肠病和肠道肿瘤的发病机制提供新的候选基因和理论依据,最终为治疗这些疾病开辟新的途径。