Regulation of Ubiquitination and Arthritis

项目概要/摘要 关节炎是一种慢性、进行性全身炎症性疾病，可导致严重的关节损伤、疼痛， 功能障碍和残疾。A20，也称为TNFAIP 3，在遗传和表观遗传学上与人类 关节炎，最近的实验研究表明A20在调节几种潜在的病理生理学 关节炎路径。携带A20缺陷树突状细胞或A20缺陷巨噬细胞/中性粒细胞的小鼠 会自发地患上关节炎A20限制了几种炎症途径，包括TLR、TNFα和 炎症信号A20如何执行这些关键功能并预防关节炎还知之甚少。 A20具有多个基序，介导去泛素化、泛素结合和E3泛素连接酶活性。的 这项提案的目的是了解A20预防关节炎的生化机制。我们有 产生了几个基因敲入小鼠品系，这些小鼠具有消除特定生物化学的战略性点突变， A20的功能使用这些新的小鼠品系，我们将确定A20的哪些泛素依赖性 这些功能保留了预防关节炎的细胞和分子途径。拟议的研究将 基于人关节炎易感蛋白建立一种新的稳健的自发性关节炎小鼠模型。

Project Summary/Abstract Arthritides are chronic, progressive systemic inflammatory diseases that lead to significant joint damage, pain, dysfunction, and disability. A20, also known as TNFAIP3, is genetically and epigenetically linked to human arthritis, and recent experimental studies implicate A20 in regulating several potential pathophysiological arthritis pathways. Mice bearing A20 deficient dendritic cells or A20 deficient macrophages/neutrophils spontaneously develop arthritis. A20 restricts several inflammatory pathways, including TLR, TNFα, and inflammasome signals. How A20 performs these critical functions and prevents arthritis are poorly understood. A20 has multiple motifs that mediate deubiquitinating, ubiquitin binding, and E3 ubiqutin ligase activities. The goal of this proposal is to understand the biochemical mechanisms by which A20 prevents arthritis. We have generated several knock-in lines of mice with strategic point mutations that abrogate specific biochemical functions of A20. Using these new mouse strains, we will determine which of A20's ubiquitin dependent functions preserve the cellular and molecular pathways that prevent arthritis. The proposed studies will establish a new robust mouse model of spontaneous arthritis based on a human arthritis susceptibility protein.