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Nucleotide Binding in NOD2-Mediated Inflammation and Carcinogenesis

NOD2 介导的炎症和癌变中的核苷酸结合

基本信息

批准号：
7753617
负责人：
JOSEPH A DUNCAN
金额：
$ 13.02万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753617
关键词：
ATP Hydrolysis ATP phosphohydrolase Acetylmuramyl-Alanyl-Isoglutamine Aloral Arthritis Bacteria Binding Binding Proteins Biochemical Biological Assay Cell Wall Chronic Crohn&apos s disease Cytokine Activation Defensins Development Disease Epithelial Event Family member Future Gastrointestinal tract structure Gene Family Genes Granulomatous Helicobacter pylori Host Defense Human Hydrolysis Immune Immune system Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inherited Intestines Investigation Label Lead Leucine-Rich Repeat Light Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Methods Microbe Modification Molecular Molecular Target Mucositis Mucous Membrane Mutation Neoplasms Nucleotides Pathogenesis Pathologic Patients Phenotype Physiological Play Predisposing Factor Predisposition Process Property Proteins Radioactive Recombinants Regulation Role Signal Transduction Signal Transduction Pathway Specificity Staging Syndrome Techniques Uveitis Variant Work antimicrobial antimicrobial peptide apoptotic protease-activating factor 1 assay development base carcinogenesis chemokine clinical application combat cytokine gastrointestinal gastrointestinal epithelium gastrointestinal system high risk in vitro Assay in vivo insight mucosa-associated lymphoid tissue lymphoma mutant nucleotide analog pathogen protein function protein protein interaction public health relevance response therapeutic target

项目摘要

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.

描述（由申请人提供）：NOD2是一种拟定的核苷酸结合蛋白，参与细菌细胞壁组分胞壁酰二肽的先天免疫识别。NOD2与人胃肠道内的慢性炎症病症有关。这些炎症性疾病现在被广泛认为是各种恶性肿瘤发展的诱发因素。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。NOD2的上皮表达也被幽门螺杆菌暴露上调。此外，克罗恩病相关的突变NOD2最近与幽门螺杆菌诱导的淋巴瘤（MALT）的发病率增加。在对细菌的生理反应期间或在疾病相关突变的情况下激活NOD2的潜在机制仍有待确定。虽然，核苷酸结合和水解是许多NOD2相关蛋白的调节中心，但这些特性尚未在NOD2中研究。对疾病相关分子靶标具有特异性的各种核苷酸类似物用于对抗许多人类疾病。我们建议：1）表征N0D 2蛋白的核苷酸结合特性，2）定义该蛋白的核苷酸结合对其功能的作用，和3）确定该过程是否被N0D 2的疾病相关突变改变。我们相信，这些研究将阐明克罗恩病的发病机制和肠道粘膜内的慢性炎症，这是与癌变。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。他们还将为未来研究NOD2功能的细节奠定基础。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。患有慢性炎症的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可以通过NOD2修饰信号传导的药理学试剂，这将在肠道炎症条件下具有临床应用。