Microglia and Uveitis

小胶质细胞和葡萄膜炎

• 批准号: 6430253
• 负责人: NARSING A RAO
• 金额: $ 34.22万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430253
• 关键词: autoimmunity; axon reaction; cell migration; confocal scanning microscopy; denervation; genetically modified animals; immunocytochemistry; immunopathology; immunoregulation; in situ hybridization; interleukin 1; interleukin 6; laboratory rat; macrophage; male; microglia; nitric oxide; optic nerve disorder; oxidative stress; peroxidation; peroxynitrites; polymerase chain reaction; rod cell; tumor necrosis factor alpha; uveitis; visual photoreceptor

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.

描述（由申请人提供）：产生的感光细胞变性 葡萄膜炎是美国失明的主要原因。这个损坏 最初被认为是由于巨噬细胞渗入 外视网膜。但是，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。 发现视网膜小胶质细胞释放活性氧和氮种， 并从内部到外视网膜/感光细胞层迁移 巨噬细胞渗透之前的EAU的早期阶段。基于这些 新发现，我们建议测试两个假设：1） 视网膜小胶质细胞激活和迁移到外部 视网膜首先发生； 2）迁移的小胶质细胞会产生炎症细胞因子， 吸引血源性吞噬细胞，包括巨噬细胞和PMN， 扩大破坏性炎症。我们将通过 遵循特定目的： 1。记录EAU和小胶质细胞迁移的自然历史 具有视神经轴切开术的Y-> X嵌合体中的感光细胞层。 2。评估细胞毒性剂（细胞因子和氧化剂）的产生 在EAU的早期迁移小胶质细胞。 3。评估小胶质细胞浸润部位的感光细胞损伤 在EAU的早期。 为了确保成功完成具体目标，我们已经组装了 多学科专家团队进行研究。 Guey-Shuaug博士Wu 在膜脂质过氧化和炎症领域具有专业知识 细胞因子。首席研究员在该领域经验丰富 实验性葡萄膜炎，眼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理中的作用可能导致 针对这些视网膜细胞的特定疗法的发展。