Nucleotide binding characteristics of disease associated mutant NOD2 proteins

摘要/概要 在这个提议中，我将把我们对野生型NOD 2的初步研究扩展到疾病相关的突变型NOD 2 proteins.我们利用NOD 2中的不同突变来剖析其分子机制， 导致NOD 2依赖性病理。NOD 2的获得性和丧失性功能突变均与 人类疾病。我们提出：1）表征疾病相关蛋白的核苷酸结合特性， NOD 2蛋白，2）定义核苷酸结合循环的作用，以确定它如何有助于NOD 2 生物学功能，和3）建立核苷酸结合或水解对生物活性的作用， 与Blau综合征（早发性结节病）和克罗恩病相关的NOD 2疾病相关突变 体内疾病我们相信这些研究将有助于阐明疾病的发病机制， 粘膜炎症旨在评估核苷酸结合特性的研究对于合理性至关重要 抑制剂的设计了解NOD 2的核苷酸结合特性可能最终导致 开发可以通过NOD 2修饰信号传导的药理学试剂，这将具有临床意义。 应用于全身和肠道炎症状况。 !

Abstract/Summary In this proposal I will extend our initial examinations with wild type NOD2 to disease-associated mutant NOD2 proteins. We have taken advantage of distinct mutations in NOD2 to dissect the molecular mechanisms that cause NOD2-dependent pathologies. Both gain- and loss-of-function mutations of NOD2 are associated with human diseases. We propose to: 1) characterize the nucleotide-binding properties of disease-associated NOD2 proteins, 2) define the role of the nucleotide binding cycle to ascertain how it contributes to NOD2 biological function, and 3) establish the role of nucleotide binding or hydrolysis on the biological activity of disease-associated mutations of NOD2 that are linked to Blau syndrome (early onset sarcoidosis) and Crohn's disease in vivo. We believe these studies will shed light on both the mechanism of disease pathogenesis and mucosal inflammation. Studies aimed at evaluating the nucleotide binding properties are crucial for rationale design of inhibitors. Understanding the nucleotide binding properties of NOD2 may ultimately lead to the development of pharmacologic agents that can modify signaling by NOD2, which would have clinical application in systemic and intestinal inflammatory conditions. !