Nucleotide binding characteristics of disease associated mutant NOD2 proteins

疾病相关突变型 NOD2 蛋白的核苷酸结合特征

• 批准号: 8626763
• 负责人: Beckley K Davis
• 金额: $ 24.64万
• 依托单位: FRANKLIN AND MARSHALL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626763
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Affect; Animals; Bacteria; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Biological Process; Bone Marrow; Catalysis; Cell Wall; Chronic; Colitis; Crohn' s disease; Data; Defensins; Development; Disease; Event; Family; Family member; Future; Gastrointestinal tract structure; Gene Family; Genes; Genetic Transcription; Host Defense; Human; Hydrolysis; Immune system; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inherited; Intestines; Label; Lead; Left; Leucine-Rich Repeat; Light; Link; Malignant neoplasm of gastrointestinal tract; Marshal; Mediating; Methods; Microbe; Modification; Molecular; Mucositis; Mucous Membrane; Mus; Mutation; Neoplasms; Nucleotides; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiological; Play; Predisposition; Process; Property; Proteins; Radioactive; Recombinants; Role; Sarcoidosis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Syndrome; Techniques; Testing; Uveitis; Variant; Work; antimicrobial; antimicrobial peptide; apoptotic protease-activating factor 1; base; chemokine; clinical application; college; cytokine; design; disease characteristic; early onset; gastrointestinal epithelium; human disease; human morbidity; human mortality; in vivo; inhibitor/antagonist; insight; leucine-rich repeat protein; loss of function mutation; macrophage; member; mutant; novel; nucleoside triphosphatase; protein protein interaction; public health relevance; reconstitution; response; therapeutic target

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. !

摘要/总结 在本提案中，我将把我们对野生型 NOD2 的初步检查扩展到与疾病相关的突变型 NOD2 蛋白质。我们利用 NOD2 的独特突变来剖析其分子机制 引起 NOD2 依赖性病理。 NOD2 的功能获得和丧失突变均与 人类疾病。我们建议：1）表征疾病相关的核苷酸结合特性 NOD2 蛋白，2) 定义核苷酸结合循环的作用，以确定它如何对 NOD2 做出贡献 生物功能，3) 确定核苷酸结合或水解对生物活性的作用 与布劳综合征（早发性结节病）和克罗恩病相关的 NOD2 疾病相关突变 体内疾病。我们相信这些研究将揭示疾病的发病机制和 粘膜炎症。旨在评估核苷酸结合特性的研究对于基本原理至关重要 抑制剂的设计。了解 NOD2 的核苷酸结合特性可能最终导致 开发可以改变 NOD2 信号传导的药物制剂，这将具有临床意义 在全身和肠道炎症条件下的应用。 ！

项目成果

The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production.

• DOI: 10.4049/jimmunol.1601370
• 发表时间: 2017-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Tocker AM;Durocher E;Jacob KD;Trieschman KE;Talento SM;Rechnitzer AA;Roberts DM;Davis BK
• 通讯作者: Davis BK