Complement System and Idiopathic Anterior Uveitis

补体系统和特发性前葡萄膜炎

• 批准号: 7898751
• 负责人: Nalini S. Bora
• 金额: $ 35.89万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898751
• 关键词: Address; Anaphylatoxins; Animal Model; Anterior eyeball segment structure; Anterior uveitis; Antigens; Applications Grants; Autoimmune Diseases; Autoimmune Process; Blindness; C3bi; C5a anaphylatoxin receptor; CD4 Positive T Lymphocytes; California; Cell physiology; Cells; Clinic; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Dendritic Cells; Development; Disease; Etiology; Eye; Future; Human; Immune; Immune response; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Investigation; Laboratories; Lead; Lymphoid; Mediating; Melanins; Membrane; Modeling; Natural Immunity; Nature; Older Population; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Phase; Play; Principal Investigator; Proteins; Publishing; Rattus; Recombinants; Recurrence; Reporting; Resolution; Role; Self-Injurious Behavior; T-Lymphocyte; Testing; Therapeutic; Tissues; United States; Uvea; Uveitis; activation product; autoimmune uveitis; base; complement system; effective therapy; epidemiology study; genetic regulatory protein; immunoregulation; in vivo; insight; lymph nodes; macrophage; monocyte; new therapeutic target; novel; prevent; public health relevance; receptor; therapeutic target; tool

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.

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 2.8% 以上的失明。北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有局限性，因为目前葡萄膜炎仅进行对症治疗。因此，需要不断的努力和未来的研究，以便预防葡萄膜炎并开发出有效且安全的未来治疗方法。特发性前葡萄膜炎（AU）是人类最常见的眼内炎症形式，该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）是一种眼睛器官特异性自身免疫性疾病，可作为特发性人类 AU 的动物模型。首席研究员 (PI) 实验室的最新研究使用 EAAU 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。在当前的提案中，PI 提议研究补体激活替代途径 (AP) 在 EAAU 发展中发挥关键作用的潜在机制，以便能够确定基于选择性阻断 AP 的新治疗靶点。目前的应用也将探讨选择性阻断补体衍生炎症介质（例如 C3a、C5a、iC3b 和膜攻击复合物 (MAC)）在 EAAU 治疗中的治疗潜力。最后，PI 打算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。该提案的具体目标是： 1. 使用实验性自身免疫性前葡萄膜炎（EAAU）动物模型研究补体激活替代途径（AP）在特发性前葡萄膜炎的发展中发挥关键作用的潜在机制。 2.探讨补体激活产物C3a、C5a、iC3b及膜攻击复合物(MAC)在特发性前葡萄膜炎发病机制中的作用。 3. 确定补体和免疫细胞之间的串扰在 EAAU 发病机制中的作用 - C3（引流淋巴结中补体的第三种成分）对免疫细胞功能的调节。拟议的研究特别密切，因为它们为充分了解补体在特发性 AU 发病机制中的作用提供了潜在的工具。此外，这些研究需要开发基于补体系统选择性调节的新型有效治疗策略。公共卫生相关性：拟议研究的结果可能会导致对人类特发性前葡萄膜炎进行更有效的管理和/或治疗。将来，补体抑制剂可能在临床上作为新型抗葡萄膜炎药物来治疗这种重要的人类眼部疾病。