Complement System and Idiopathic Anterior Uveitis

描述（由申请人提供）：当前提案的长期目标是发现葡萄膜炎的根本原因和病因，并找到治疗这种疾病的方法，这种疾病导致美国超过2.8%的失明。北方加州流行病学研究最近的一份报告表明，美国老年人口的患病率较高。不幸的是，葡萄膜炎患者可用的治疗选择具有局限性，因为目前葡萄膜炎仅通过手术治疗。因此，需要持续的努力和未来的研究，以预防葡萄膜炎，并为未来开发有效和安全的治疗方法。特发性前葡萄膜炎（Au）是人类眼内炎症的最常见形式，并且该疾病的复发性质可导致永久性视力丧失。实验性自身免疫性前葡萄膜炎（Experimental autoimmune anterior uveitis，EA Au）是一种眼器官特异性自身免疫性疾病，可作为人类特发性Au的动物模型。主要研究者（PI）实验室的最新研究已经使用EA Au动物模型确定了补体和补体调节蛋白（CReg）在特发性Au发病机制中的关键作用。在当前提案中，PI建议研究补体激活的旁路途径（AP）在EAAU发展中发挥关键作用的潜在机制，以便确定基于AP选择性阻断的新型治疗靶点。在本申请中还将探索选择性阻断补体衍生的炎症介质如C3 a、C5 a、iC 3b和膜攻击复合物（MAC）在治疗EAAU中的治疗潜力。最后，PI打算确定补体和免疫细胞之间的相互作用在EAAU发病机制中的重要性。该提案的具体目标是：1.目的：利用实验性自身免疫性前葡萄膜炎（EAAU）动物模型，探讨补体激活旁路途径（AP）在特发性前葡萄膜炎（EAAU）发病中的作用机制。2.探讨补体激活产物C3 a、C5 a、iC 3b及膜攻击复合物（MAC）在特发性前葡萄膜炎发病中的作用。3.确定补体和免疫细胞之间的相互作用在EAAU发病机制中的作用-引流淋巴结中补体的第三组分C3对免疫细胞功能的调节。拟议的研究是特别密切相关的，因为他们提供了潜在的工具，以充分了解的作用，补体在特发性Au的发病机制。此外，这些研究是必要的，以开发新的有效的治疗策略的基础上选择性调节补体系统。公共卫生相关性：从拟议的研究中得出的结果可能会导致更有效的管理和/或治疗人类特发性前葡萄膜炎。在未来，补体抑制剂可能会被用作新的抗葡萄膜炎药物在临床上用于治疗这种重要形式的人类眼部疾病。

DESCRIPTION (provided by applicant): Long-term objectives of the current proposal are to discover the fundamental causes and etiologic factors responsible for uveitis as well as to find a cure for this disease, which is responsible for over 2.8% of blindness in the United States. A recent report from the Northern California Epidemiology Study suggested a higher disease rate for the older population in US. Unfortunately, treatment options available to uveitis patients have limitations because currently uveitis is treated symptomatically only. Therefore, continuous efforts and future investigations are needed so that uveitis could be prevented and efficient and safe therapies for future could be developed. Idiopathic anterior uveitis (AU) is the most common form of intraocular inflammation in humans and the recurrent nature of the disease can lead to permanent visual loss. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye which serves as an animal model of idiopathic human AU. Recent studies from the Principal Investigator's (PI) laboratory have identified a critical role of complement and complement regulatory proteins (CRegs) in the pathogenesis of idiopathic AU using EAAU animal model. In the current proposal the PI proposes to investigate the underlying mechanisms by which alternative pathway (AP) of complement activation plays a crucial role in the development of EAAU so that novel therapeutic targets based on selective blockade of AP could be identified. Therapeutic potential of selective blockade of complement derived inflammatory mediators such as C3a, C5a, iC3b and membrane attack complex (MAC) in the treatment of EAAU will also be explored in the current application. Finally, the PI intends to determine the importance of cross-talk between complement and immune cells in the pathogenesis of EAAU. The specific aims of this proposal are: 1. To investigate the underlying mechanisms by which alternative pathway (AP) of complement activation plays a crucial role in the development of idiopathic anterior uveitis using experimental autoimmune anterior uveitis (EAAU) animal model. 2. To explore the role of complement activation products - C3a, C5a, iC3b and membrane attack complex (MAC) in the pathogenesis of idiopathic anterior uveitis. 3. To determine the role of cross-talk between complement and immune cells in the pathogenesis of EAAU - Modulation of immune cell function by C3, the third component of complement in draining lymph nodes. The proposed studies are particularly germane because they provide potential tools to fully understand the role of complement in the pathogenesis of idiopathic AU. Furthermore, these studies are required for the development of novel effective therapeutic strategies based on selective modulation of complement system. PUBLIC HEALTH RELEVANCE: The results derived from the proposed study may lead to more effective management and/or treatment of human idiopathic anterior uveitis. In future, complement inhibitors might be used as novel antiuveitic agents in the clinic for the treatment of this important form of human ocular disease.