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导致葡萄膜炎的根本原因和病因学因素，并找到治疗这种疾病的方法，在美国，葡萄膜炎导致超过2.8%的失明。北加州流行病学研究最近的一份报告显示，美国老年人的发病率更高。不幸的是，葡萄膜炎患者的治疗选择有局限性，因为目前葡萄膜炎只能对症治疗。因此，为了预防葡萄膜炎和开发有效、安全的治疗方法，需要持续的努力和未来的研究。特发性前葡萄膜炎（AU）是人类最常见的眼内炎症，这种疾病的复发性可导致永久性视力丧失。实验性自身免疫性前葡萄膜炎（EAAU）是一种器官特异性的眼部自身免疫性疾病，是人类特发性前葡萄膜炎的动物模型。最近，来自首席研究员（PI）实验室的研究利用EAAU动物模型确定了补体和补体调节蛋白（CRegs）在特发性AU发病机制中的关键作用。在目前的提案中，PI建议研究补体激活的替代途径（AP）在EAAU发展中发挥关键作用的潜在机制，从而确定基于选择性阻断AP的新治疗靶点。选择性阻断补体源性炎症介质如C3a、C5a、iC3b和膜攻击复合物（MAC）在EAAU治疗中的治疗潜力也将在目前的应用中探索。最后，该项目旨在确定补体和免疫细胞之间的串扰在EAAU发病机制中的重要性。本建议的具体目的是：1。利用实验性自身免疫性葡萄膜炎（EAAU）动物模型，探讨补体激活的替代途径（AP）在特发性葡萄膜炎发展中发挥重要作用的潜在机制。2. 探讨补体活化产物C3a、C5a、iC3b和膜攻击复合物（MAC）在特发性前葡萄膜炎发病中的作用。3. 探讨补体与免疫细胞间的串扰在EAAU发病机制中的作用——补体第三组分C3对免疫细胞功能的调节作用。提出的研究是特别相关的，因为它们提供了潜在的工具，以充分了解补体在特发性AU发病机制中的作用。此外，这些研究还需要基于补体系统的选择性调节来开发新的有效的治疗策略。公共卫生相关性：拟议研究的结果可能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，补体抑制剂可能被用作临床治疗这种重要的人类眼部疾病的新型抗葡萄晶体药物。

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.