Monarch/NLRP12: A Newly discovered Innate Immune Receptor in Uveitis

 描述（由申请人提供）：由于葡萄膜炎是世界范围内致盲的主要原因之一，因此迫切需要确定葡萄膜炎的关键潜在机制。眼部炎症性疾病的发病率越来越高，需要更有效和创新的治疗方法。不幸的是，虽然目前可用的药物有助于减少炎症，但它们不能治愈疾病。为了更好的治疗方法，我们需要了解导致疾病的启动和早期事件的基本机制。预期参与炎症起始的此类信号涉及由微生物触发物激活的先天免疫受体。当前的范例被认为是NEI的使命目标：“了解先天免疫和适应性免疫在眼部炎症中的相互作用”和“评估先天免疫在葡萄膜炎中的作用”。“这项旨在推进NEI使命的提案将解决先天免疫受体NLRP 12如何参与抑制眼部炎症的免疫反应。NOD样受体（NLR）如NLRP 12在眼睛中的功能知之甚少，但这个以前未被考虑的先天免疫受体家族可能是眼睛内源性保护的一个关键方面。本研究的目的是（1）检验NLRP 12在控制眼内局部激活的TLR应答中发挥重要的负调节作用的假设;和（2）检验NLRP 12对减轻葡萄膜原性T细胞应答和自身免疫性葡萄膜炎的发展至关重要的假设。分子和细胞的方法结合慢性实验性葡萄膜炎在小鼠中建模应该告诉我们如何NLRP 12依赖性先天反应参与协调的适应性免疫反应和控制易感性葡萄膜炎。该应用基于疾病免疫学基础中的最新概念和研究，并且可以改变考虑眼部炎症状况的范式，因为它关注先天信号如何参与关闭炎症，而不是促进炎症。深入研究内源性眼部保护机制的拟议研究结果可能为葡萄膜炎和其他潜在视力威胁疾病的治疗开发开辟新途径。

 DESCRIPTION (provided by applicant): There is a pressing need to define key underlying mechanisms in uveitis because it is one of the leading causes of blindness worldwide. Increasingly high incidences of ocular inflammatory diseases demand more effective and innovative treatments. Unfortunately, while currently available medications help reduce inflammation, they do not offer a cure for disease. For a better therapeutic approach, we need to understand the basic mechanisms in initiation and early events that lead to disease. Such signals involved in initiation of inflammation are expected to involve innate immune receptors activated by microbial triggers. This current paradigm is recognized as an NEI Mission goal: "understand the interaction between innate and adaptive immunity in ocular inflammation" and "evaluate the role of innate immunity in uveitis." This proposal--that aims to advance the mission of NEI--will address how the innate immune receptor, NLRP12, is involved in immune responses that suppress ocular inflammation. Very little is understood how NOD-like receptors (NLRs) such as NLRP12 function in the eye, but this previously unconsidered family of innate immune receptors may be a critical aspect of endogenous protection of the eye. The objectives of this study will (1) Test the hypothesis that NLRP12 exerts an important negative regulatory role in controlling TLR-responses activated locally within the eye; and (2) Test the hypothesis that NLRP12 is essential to mitigation of uveitogenic T cell responses and development of autoimmune uveitis. The molecular and cellular approaches combined with chronic experimental uveitis modeled in mice should inform us as to how NLRP12-dependent innate responses are involved in orchestration of adaptive immune responses and controlling susceptibility to uveitis. This application is based upon the most current concepts and research in immunological basis of disease and could shift the paradigm within which ocular inflammatory conditions are considered because it focuses on how innate signals may be involved in shutting off inflammation, rather than promoting inflammation. Results of the proposed studies delving into endogenous ocular protective mechanisms could open up new avenues for development of therapies for uveitis and potentially for other vision-threatening diseases.