NOD2 and Uveitis

NOD2 和葡萄膜炎

• 批准号: 7730112
• 负责人: HOLLY Lallman ROSENZWEIG
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730112
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Affect; Agonist; Bacteria; Base Pairing; Biological; Biological Assay; Blindness; Bone Marrow; Caspase-1; Cells; Chimera organism; Clinical; Crohn' s disease; Cross Infection; Disease; Endotoxins; Etiology; Eye; Family; Family member; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Granuloma; Granulomatous; Histology; Homologous Gene; Human Biology; IRF1 gene; Immune; Immune system; Immunohistochemistry; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Inherited; Interferons; Interleukin-1; Joints; Knowledge; Lead; Leukocytes; Light; Link; Measurable; Mediating; Mediator of activation protein; Modeling; Mus; Mutation; Nature; Pathogenesis; Pathway interactions; Penetrance; Peptidoglycan; Peripheral; Phosphotransferases; Play; Production; Proteins; Publications; RIPK2 gene; Regulation; Reporting; Role; STAT1 gene; Sarcoidosis; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Syndrome; TLR2 gene; TLR4 gene; Techniques; Testing; Time; Toll-like receptors; Uveitis; abstracting; anakinra; base; in vivo; insight; intravital microscopy; member; novel; public health relevance; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT. The underlying mechanisms of uveitis, or intraocular inflammation, remain poorly understood. However, a recently identified gene called NOD2 provides important insight into the genetics involved in the pathogenesis of uveitis. Specific mutations within NOD2 are the cause of an inherited multisystem granulomatous disease affecting the eye, joints and skin that develop in the absence of infection. While pathogenic mutations have been identified, the functions of NOD2 responsible for initiation of ocular inflammation have not. We have succeeded in establishing a model of NOD2-dependent uveitis, wherein NOD2 is activated by its synthetic agonist muramyl dipeptide (MDP). We propose to use this model to investigate the mechanisms by which NOD2 could initiate uveitis either via its direct activation by its agonist (in the absence of infection as might occur in Blau syndrome) or by its ability to regulate inflammation induced by either toll-like receptors (TLRs) or by the homologous family member, NOD1. Specifically, we will 1) Identify which cells respond to MDP and investigate the role of IFNg as a modulator of NOD2-driven ocular inflammation; 2) Since our discovery that NOD1 triggers uveitis, we propose to investigate whether NOD1 and NOD2-induced ocular inflammatory response are distinguishable and whether cross-talk occurs; and 3) Since NOD2 appears to exert its most measurable biological effects when it modulates TLRs, we will explore the capacity of NOD2 to regulate TLR responses within the eye. This aim will also explore how MDP affects the inflammatory response triggered by IL-1b. Together, these studies will have considerable implications for understanding pathological mechanisms involved in uveitis. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE/SIGNIFICANCE. "Experiments" in nature can lead to personal suffering while concomitantly offering unique opportunities to elucidate human biology. This is best exemplified in Blau syndrome, wherein a single base pair change in the NOD2 gene results in complete penetrance for the induction of uveitis and multisystem granulomatous disease. The connection between a single gene and uveitis offers enormous potential to study the pathogenesis of uveitis.

描述(由申请人提供)： 项目摘要/摘要。葡萄膜炎或眼内炎症的潜在机制仍然知之甚少。然而，最近发现的一种名为NOD2的基因为葡萄膜炎发病的遗传学提供了重要的见解。NOD2中的特定突变是一种遗传性多系统肉芽肿疾病的原因，这种疾病在没有感染的情况下会影响眼睛、关节和皮肤。虽然已经确定了致病突变，但负责启动眼部炎症的NOD2的功能尚未确定。我们成功地建立了一种NOD2依赖的葡萄膜炎模型，其中NOD2由其合成激动剂胞壁二肽(MDP)激活。我们建议使用这个模型来研究NOD2通过它的激动剂直接激活(在没有感染的情况下可能发生在BLAU综合征中)或者通过它调节由Toll样受体(TLRs)或由同源家族成员NOD1引起的炎症的机制。具体地说，我们将1)确定哪些细胞对MDP有反应，并研究IFNG作为NOD2驱动的眼部炎症的调节器的作用；2)由于我们发现NOD1触发葡萄膜炎，我们建议调查NOD1和NOD2诱导的眼部炎症反应是否可区分以及是否存在串扰；以及3)由于NOD2似乎在调节TLR时发挥其最可测量的生物学效应，我们将探索NOD2调节眼睛内TLR反应的能力。这一目标还将探索MDP如何影响IL-1b引发的炎症反应。总之，这些研究将对了解葡萄膜炎的病理机制有相当大的意义。公共卫生相关性：项目叙述/意义。自然界中的“实验”可能会导致个人痛苦，同时也提供了阐明人类生物学的独特机会。这在BLAU综合征中是最好的例证，在BLAU综合征中，NOD2基因的单个碱基对改变导致完全外露，从而诱导葡萄膜炎和多系统肉芽肿疾病。单个基因与葡萄膜炎之间的联系为研究葡萄膜炎的发病机制提供了巨大的潜力。