The role of the innate and adaptive immune system in a novel model of uveit

描述(申请人提供)：葡萄膜炎是导致视力丧失的重要原因，在美国排名第五位的失明原因。葡萄膜炎引起的炎症会导致眼部损害，包括青光眼、黄斑水肿、白内障、视网膜前膜和持续性中膜混浊。葡萄膜炎的治疗并不理想；大多数葡萄膜炎是用皮质类固醇治疗的，这是一种有效的非特异性药物，严重的眼部和全身并发症的发生率很高。本研究旨在了解AIFU小鼠模型中自身炎性葡萄膜炎的发病机制。我的目标是深入了解先天性免疫系统在眼部炎症中所起的作用，以便开发新的治疗方法，以防止葡萄膜炎患者的视力丧失和失明。我们的核心假设是，AIFU模型是一种具有混合先天免疫和获得性免疫特征的自体炎症人类葡萄膜炎的动物模型。我建议将AIFU模型从大鼠移植到小鼠身上，以获取该动物模型中可用的遗传工具，并开发一种新的实时报告系统来检测和监测体内的眼部炎症。利用小鼠的遗传和免疫学分析，我将确定先天免疫系统和获得性免疫系统在这种自发性炎症性葡萄膜炎模型中的作用，并确定Mueller胶质细胞在眼部炎症反应中的作用。针对这一中心假设提出了三个具体目标：1)建立包括实时眼部炎症报告系统在内的AIFU小鼠模型。2)确定Mueller神经胶质细胞在AIFU炎症中的作用。3)确定先天免疫反应和获得性免疫反应对AIFU的贡献。作为一名在葡萄膜炎领域执业的学术眼科医生，我对了解眼部炎症的机制具有临床和研究兴趣。作为华盛顿大学的一名研究员和教员，我的临床专业将是治疗葡萄膜炎患者，我的研究项目将研究眼部炎症，重点是先天性免疫系统。眼科和华盛顿大学眼科研究所拥有世界一流的教师和设施，这将帮助我充分发展成为一名临床医生和科学家。随着我事业的发展，我将受益于经验丰富的科学家和临床医生的密切指导，他们深深地致力于我的成功。

DESCRIPTION (provided by applicant): Uveitis is an important cause of vision loss ranking fifth among causes of blindness in the United States. The inflammation that occurs in uveitis leads to ocular damage including glaucoma, macular edema, cataract, epiretinal membranes, and persistent media opacity. Treatments for uveitis are suboptimal; most uveitis is treated with corticosteroids, which are potent, non-specific agents that have high rates of serious ocular and systemic complications. This work aims to understand the mechanisms of autoinflammatory uveitis in the AIFU mouse model. My goal is to gain insights into the roles the innate immune system plays in ocular inflammation in order to develop novel therapeutic approaches that could prevent vision loss and blindness in patients with uveitis. Our core hypothesis is that the AIFU model serves as an animal model of autoinflammatory human uveitis with mixed innate and adaptive immune features. I propose to port the AIFU model from rats to mice to access the genetic tools available in this animal model, and to develop a novel real time reporter system to detect and monitor ocular inflammation in vivo. Using mouse genetic and immunologic assays, I will identify the contribution of the innate and adaptive immune systems to this model of autoinflammatory uveitis, and determine the role of the Mueller glia in the ocular inflammatory response. Three specific aims are proposed to address the central hypothesis: 1) Generate the AIFU mouse model including a real time ocular inflammation reporter system. 2) Determine the role of the Mueller glia in AIFU inflammation. 3) Determine the contribution of the innate and adaptive immune response to AIFU. As an academic ophthalmologist practicing in the field of uveitis, I have both a clinical and research interest in understanding the mechanisms of ocular inflammation. As a fellow and then faculty member at the University of Washington, my clinical specialty will be treating patients with uveitis and my research program will study ocular inflammation with a focus on the innate immune system. The Department of Ophthalmology and the University of Washington Eye Institute has a world-class faculty and facilities that will help me to fully develop as a clinician-scientist. As my career develops, I will benefit from close mentoring by experienced scientists and clinicians who are deeply committed to my success.