非可控炎症是糖尿病、癌症等多种重大疾病的主要诱因，调控紊乱是造成炎症处于非可控状态的重要原因。NF-kB能诱导一系列炎症相关蛋白表达，在炎症反应调控中发挥核心作用，其活性的正常维持对相关疾病防治有重要意义。Betatrophin是一个新发现的参与糖脂代谢的分泌蛋白，但其是否参与NF-kB活性调控尚无报道。申请人前期工作发现该蛋白的表达不仅在2型糖尿病患者血清中随病情恶化上调，且在细胞水平受糖尿病相关促炎症因子TNFa的诱导，并能抑制TNFa或IL-1b诱导的NF-kB激活，该作用可能是通过在细胞内对IKK激酶复合物等靶标的调控介导。本项目计划进一步锁定Betatrophin的分子靶标，解析其调控NF-kB激活的具体机制，探讨其是否通过调控NF-kB活性而影响胰岛素通路。该研究有望揭示一种NF-kB活性调控的新机制，从而为糖尿病等炎症相关疾病的治疗提供理论依据。

Nonresolving inflammation, which is closely associated with the dysregulation of inflammation, is a key driver of multiple major diseases. NF-kB is a transcription factor that plays pivotal roles in the regulation of inflammation through responding to various stimuli and lead to the expression of various inflammatory proteins. Therefore, the normal activity of NF-kB is critical to the prevention and control of major inflammation-related diseases. Betatrophin is a newly identified secreted protein which is involved in glucose and lipid metabolisms, its relationship with the regulation of NF-kB activation has not been reported. In our pilot study, we found the expression level of Betatrophin was positively associated with the progression of type 2 diabetes, moreover, it could be induced by the pro-inflammatory cytokine TNFa. In addition, we found Betatrophin could inhibit TNFa- or IL-1b-induced NF-kB activation, and such effects may be mediated by targeting IKK kinase complex. In this study, we propose to identify the molecular target of Betatrophin in its inhibition of TNFa- or IL-1b-induced NF-kB activation, to investigate its regulation mechanisms and study whether Betatrophin has any effect in insulin signal pathway through regulating the activity of NF-kB. This work may reveal a new molecular mechanism of the regulation of NF-kB activation, and provide new insights into the mechanisms for inflammatory diseases such as diabetes.