Microglia and Uveitis

描述(申请人提供)：感光细胞变性 葡萄膜炎是美国人失明的主要原因。这一损害 最初被认为是由于巨噬细胞渗透到 外视网膜。然而，我们的初步研究表明，视网膜小胶质细胞 可能是引发葡萄膜炎的细胞，导致随后的视网膜损伤。 视网膜小胶质细胞释放出活性氧和氮物质， 和迁移从内到外视网膜/光感受器细胞层 早期EAU出现在巨噬细胞浸润之前。基于这些 新的发现，我们建议检验两个假设：1)在自身免疫中 葡萄膜视网膜炎与视网膜小胶质细胞的活化和外移 视网膜首先出现；2)迁移的小胶质细胞产生炎性细胞因子， 吸引血源性吞噬细胞，包括巨噬细胞和中性粒细胞，这些细胞 放大破坏性炎症。我们将使用 以下是具体目标： 1.记录EAU和小胶质细胞迁移到 视神经切断后Y-X嵌合体中的感光细胞层。 2.通过评估细胞毒剂(细胞因子和氧化剂)的生成 EAU早期有小胶质细胞迁移。 3.评估小胶质细胞浸润部位的光感受器细胞损伤 在EAU的早期阶段。 为了确保顺利完成特定目标，我们已组建了一个 由多学科专家团队承担这项研究。吴贵硕博士 在膜脂过氧化和炎症领域具有专业知识 细胞因子。首席调查员在以下领域经验丰富 实验性葡萄膜炎、眼部病理学和自由基生物学。理解 视网膜小胶质细胞在葡萄膜炎发病机制中的作用可能导致 针对这些视网膜细胞的特异性治疗的发展。

DESCRIPTION (provided by applicant): Photoreceptor cell degeneration resulting from uveitis is a major cause of blindness in the United States. This damage was initially believed to be due to the infiltration of macrophages into the outer retina. However, our preliminary studies suggest that retinal microglia could be the cells that initiate uveitis, leading to subsequent retinal damage. Retinal microglia were found to release reactive oxygen and nitrogen species, and to migrate from inner to outer retina/photoreceptor cell layer during the early phase of EAU prior to the infiltration of macrophages. Based on these novel findings, we propose to test two hypotheses: 1) In autoimmmune uveo-retinitis, activation and migration of retinal microglia to the outer retina occur first; 2) The migrated microglia generate inflammatory cytokines, attracting hematogenous phagocytes, including macrophages and PMNs, which amplify the destructive inflammation. We will test these hypotheses with the following Specific Aims: 1. Document the natural history of EAU and microglial migration to the photoreceptor cell layer in Y->X chimeras with optic nerve axotomy. 2. Evaluate generation of cytotoxic agents (cytokines and oxidants) by the migrated microglia in the early phase of EAU. 3. Evaluate photoreceptor cell damage at the site of microglial infiltration during the early phase of EAU. To assure successful completion of the specific aims, we have assembled a multidisciplinary team of experts to undertake the studies. Dr. Guey-Shuaug Wu has expertise in the areas of membrane lipid peroxidation and inflammatory cytokines. The principal investigator is experienced in the field of experimental uveitis, ocular pathology and free radical biology. Understanding the role of retinal microglia in the pathogenesis of uveitis could lead to the development of specific therapy directed against these retinal cells.