Regulation of Ubiquitination and Arthritis

项目摘要/摘要 关节炎是一种慢性、进行性全身性炎症性疾病，会导致严重的关节损伤、疼痛、 功能障碍和残疾。A20，也被称为TNFAIP3，在基因和表观遗传上与人类有关联 关节炎，以及最近的实验研究表明A20参与了几种潜在的病理生理调节 关节炎的路径。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 自发性地患上关节炎。A20可限制多种炎症途径，包括TLR、肿瘤坏死因子α和 发炎的信号。A20是如何发挥这些关键功能并预防关节炎的，目前还知之甚少。 A20具有多个基序，介导脱泛素、泛素结合和E3泛素连接酶活性。这个 这项建议的目标是了解A20预防关节炎的生化机制。我们有 产生了几个带有策略性点突变的小鼠敲入系，这些突变消除了特定的生化 A20的功能。使用这些新的小鼠品系，我们将确定A20‘S泛素依赖于哪一个 这些功能保护了预防关节炎的细胞和分子途径。拟议的研究将 基于人类关节炎易感蛋白建立一种新的健壮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.