NOD2 and Uveitis

描述（由申请人提供）： 项目总结/摘要。葡萄膜炎或眼内炎症的潜在机制仍然知之甚少。然而，最近发现的一个称为NOD 2的基因为葡萄膜炎发病机制中涉及的遗传学提供了重要的见解。NOD 2内的特定突变是影响眼睛、关节和皮肤的遗传性多系统肉芽肿性疾病的原因，这些疾病在没有感染的情况下发展。虽然致病性突变已被确定，但负责引发眼部炎症的NOD 2的功能尚未确定。我们已经成功地建立了NOD 2依赖性葡萄膜炎模型，其中NOD 2被其合成激动剂胞壁酰二肽（MDP）激活。我们建议使用这个模型来研究NOD 2可以通过其激动剂直接激活（在没有感染的情况下，可能发生在Blau综合征）或通过其调节由Toll样受体（TLR）或同源家族成员NOD 1诱导的炎症的能力来引发葡萄膜炎的机制。具体而言，我们将1）鉴定哪些细胞对MDP应答，并研究IFNg作为NOD 2驱动的眼部炎症的调节剂的作用; 2）由于我们发现NOD 1触发葡萄膜炎，我们建议研究NOD 1和NOD 2诱导的眼部炎症反应是否是可区分的，以及是否发生串扰;由于NOD 2在调节TLR时发挥其最可测量的生物学效应，我们将探索NOD 2调节眼内TLR反应的能力。这一目标还将探讨MDP如何影响IL-1b引发的炎症反应。总之，这些研究将有相当大的影响，了解葡萄膜炎的病理机制。公共卫生相关性：项目叙述/意义。自然界中的“实验”可能导致个人痛苦，同时也提供了独特的机会来阐明人类生物学。这在Blau综合征中得到最好的例证，其中NOD 2基因中的单个碱基对变化导致诱导葡萄膜炎和多系统肉芽肿性疾病的完全失活。单一基因与葡萄膜炎的关系为研究葡萄膜炎的发病机制提供了巨大的潜力。

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.