Uveitogenic Epitope(s) and Idiopathic Anterior Uveitis

描述(由申请人提供)：目前这项提案的长期目标是研究葡萄膜炎的根本原因和病因，并找到治疗这种疾病的方法。北加州流行病学研究最近的一份报告表明，美国老年人口的发病率更高。不幸的是，葡萄膜炎患者可用的治疗选择是有限的，因为目前葡萄膜炎只对症治疗。因此，需要不断的努力和未来的研究来开发有效和安全的治疗方法。特发性前葡萄膜炎(IAU)是人类最常见的眼内炎症形式，该病的反复发作可导致永久性视力丧失。实验性自身免疫性前葡萄膜炎(EAAU)是一种眼部器官特异性自身免疫性疾病，是人类IAU的动物模型。首席调查员(PI)实验室的研究证实，EAAU中的黑色素相关抗原(MAA)是I型胶原蛋白-2链的22 kDa片段[CI-？2(22 KDa)]。在目前的拨款方案中，PI建议准确地确定MAA中对葡萄膜致病性至关重要的表位(S)，确定MHC结合和TCR接触残基，并探索改变的多肽配体(APL)是否可以抑制EAAU。本方案的具体目的是：特异性目的1：确定葡萄膜促葡萄膜抗原表位(S)[(CI-2(22 KDa)])特异性目的2：研究哪些氨基酸在EAAU中起关键作用以及改变的多肽配体(APL)在前葡萄膜炎2A型中的作用。MHC和TCR接触性氨基酸2B的鉴定APL的产生及其对EAAU的抑制作用。建议的研究特别贴切，因为它们将提供与IAU病因发病机制相关的关键信息。此外，这些研究将促进基于抗原的人类IAU治疗干预措施的发展，而IAU与显著的发病率相关。

DESCRIPTION (provided by applicant): Long-term objectives of the current proposal are to study the fundamental causes and etiologic factors responsible for uveitis as well as to find a cure for this disease. A recent report from the Northern California Epidemiology Study suggested a higher disease rate for the older population in the 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 to develop efficient and safe therapies. Idiopathic anterior uveitis (IAU) is the most common form of intraocular inflammation in humans and the recurrent nature of the disease can lead to permanent loss of vision. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye which serves as an animal model of human IAU. Studies from the Principal Investigator's (PI) laboratory have established that melanin associated antigen (MAA), autoantigen in EAAU is a 22 kDa fragment of type I collagen ¿-2 chain [CI- ¿2 (22 kDa)]. In the current grant proposal the PI proposes to precisely identify the epitope(s) in MAA that is/are crucial for the uveitogenicity, determine MHC binding and TCR contact residues and explore if EAAU can be inhibited by Altered Peptide Ligands (APLs). The specific aims of this proposal are: Specific Aim 1: To identify uveitogenic epitope(s) of MAA [(CI-¿2 (22 kDa)] Specific Aim 2: To investigate which amino acids are crucial for EAAU and role of Altered Peptide Ligands (APLs) in anterior uveitis 2A. Identification of MHC and TCR contact amino acids 2B. Generation of APLs and inhibition of EAAU by APLs. The proposed studies are particularly germane because they would provide critical information related to etio-pathogenesis of IAU. Additionally, these studies will facilitate the development of antigen based therapeutic interventions for human IAU which is associated with significant morbidity.