Nucleotide Binding in NOD2-Mediated Inflammation and Carcinogenesis

描述（由申请人提供）：NOD2是一种被提议的核苷酸结合蛋白，参与细菌细胞壁成分muramyl二肽的先天免疫识别。NOD2与人类胃肠道内的慢性炎症有关。这些炎症条件现在被广泛认为是各种恶性肿瘤发展的易感因素。编码这种NOD2的基因突变与克罗恩病的易感性有关，克罗恩病是炎症性肠病的两种主要形式之一。上皮细胞NOD2的表达也因幽门螺杆菌暴露而上调。此外，克罗恩病相关的NOD2突变最近与幽门螺杆菌诱导的淋巴瘤（MALT）发病率增加有关。在对细菌的生理反应中或在疾病相关突变的环境中，NOD2激活的机制仍有待确定。尽管核苷酸结合和水解是许多NOD2相关蛋白调控的核心，但这些特性尚未在NOD2中得到研究。对疾病相关分子靶点具有特异性的各种核苷酸类似物被用于对抗许多人类疾病。我们建议：1)表征NOD2蛋白的核苷酸结合特性，2)定义该蛋白与核苷酸结合对其功能的作用，以及3)确定该过程是否会因NOD2的疾病相关突变而改变。我们相信这些研究将揭示克罗恩病的发病机制和肠道黏膜慢性炎症与癌变有关的机制。这些研究对于进一步了解NOD2活性的调控具有重要意义。他们将回答有关NOD2突变引起的疾病的分子机制的基本问题。它们还将为未来对NOD2功能细节的研究奠定基础。公共卫生相关性：NOD2是一种核苷酸结合蛋白，参与启动和维持胃肠道系统内的炎症。慢性炎症患者患多种疾病的风险更高，包括癌症的发展。了解NOD2的核苷酸结合特性可能最终导致开发能够修饰NOD2信号传导的药物，从而在肠道炎症条件下具有临床应用价值。

DESCRIPTION (provided by applicant): NOD2 is a proposed nucleotide-binding protein involved in the innate immune recognition of the bacterial cell wall components, muramyl dipeptide. NOD2 is implicated in conditions of chronic inflammation within the human gastrointestinal tract. These inflammatory conditions are now widely recognized as predisposing factors in the development of various malignancies. Mutations in the gene encoding this NOD2 have been linked to susceptibility to Crohn's Disease, one of two primary forms of Inflammatory Bowel Disease. Epithelial expression of NOD2 is also upregulated by Helicobacter pylori exposure. Additionally, a Crohn's disease associated mutation in NOD2 was recently linked to increased incidence of the Helicobacter pylori-induced lymphoma (MALT). The mechanisms underlying the activation of NOD2 during physiologic responses to bacteria or in the setting of disease-associated mutations remain to be determined. Though, nucleotide binding and hydrolysis are central to the regulation of many NOD2 related proteins, these properties have not been studied in NOD2. Various nucleotide analogs with specificity for disease associated molecular targets are used to combat many human illnesses. We propose to: 1) characterize the nucleotide-binding properties of NOD2 proteins, 2) define the role nucleotide binding by this protein contributes to its function, and 3) establish whether this process is altered by disease- associated mutations of NOD2. We believe these studies will shed light on both the mechanism of Crohn's Disease pathogenesis and chronic inflammation within the gut mucosa, which is associated with carcinogenesis. These studies are important to further our understanding of the regulation of NOD2 activity. They will answer fundamental questions regarding the molecular mechanisms underlying diseases caused by NOD2 mutations. They will also set the stage for future investigations into the details of NOD2 function. PUBLIC HEALTH RELEVANCE: NOD2 is a nucleotide binding protein involved in initiating and maintaining inflammation within the gastrointestinal system. Patients with chronic inflammation are at higher risk for numerous conditions including the development of cancers. 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 intestinal inflammatory conditions.