Microglia and Uveitis

描述（由申请人提供）：感光细胞变性导致 在美国，葡萄膜炎是导致失明的主要原因。这种损害 最初认为是由于巨噬细胞浸润到 外视网膜然而，我们的初步研究表明， 可能是引发葡萄膜炎的细胞，导致随后的视网膜损伤。 发现视网膜小胶质细胞释放活性氧和氮类， 并在视网膜/感光细胞层的生长过程中从视网膜/感光细胞层的内层迁移到外层 巨噬细胞浸润前的EAU早期。基于这些 新的发现，我们提出测试两个假设：1）在自身免疫 葡萄膜视网膜炎，视网膜小胶质细胞的激活和迁移到外部 视网膜首先发生; 2）迁移的小胶质细胞产生炎性细胞因子， 吸引造血吞噬细胞，包括巨噬细胞和中性粒细胞， 放大了破坏性的炎症我们将测试这些假设与 具体目标： 1.记录EAU和小胶质细胞迁移至 Y-> X嵌合体视神经轴突切断的感光细胞层。 2.评价细胞毒性剂（细胞因子和氧化剂）的生成， EAU早期小胶质细胞迁移。 3.评估小胶质细胞浸润部位的感光细胞损伤 在EAU的早期阶段。 为确保各项目标得以顺利完成，我们已 多学科专家小组进行研究。Guey-Shuaug Wu博士 在膜脂质过氧化和炎症领域具有专长 细胞因子主要研究者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 开发针对这些视网膜细胞的特异性治疗。

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.