IN VIVO ROLE OF CAVEOLIN-1 IN MODULATING PHOTORECEPTOR FUNCTION

CAVEOLIN-1 在调节光感受器功能中的体内作用

• 批准号: 8360406
• 负责人: MICHAEL R. ELLIOTT
• 金额: $ 5.53万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360406
• 关键词: Bone Marrow; Cells; Centers of Research Excellence; Diabetic Retinopathy; Environment; Eye; Flow Cytometry; Funding; Future; Grant; Immune response; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Ligands; Lipopolysaccharides; Maintenance; Mediating; Membrane; Mentors; Messenger RNA; Microarray Analysis; National Center for Research Resources; Natural Immunity; Oklahoma; Photoreceptors; Play; Principal Investigator; Receptor Signaling; Regulation; Research; Research Infrastructure; Resources; Retina; Retinal; Role; Signal Transduction; Source; TLR4 gene; Tertiary Protein Structure; Testing; Toll-like receptors; United States National Institutes of Health; Vision research; autoimmune uveitis; caveolin 1; cost; in vivo; research study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent evidence outside of the eye indicates that the membrane domain protein, caveolin-1 (Cav-1) modulates inflammatory responses and innate immunity through regulation of Toll-like receptor (TLR) signaling. In autoimmune uveitis and diabetic retinopathy, conditions that share robust retinal inflammation as a pathological component, Cav-1 expression is dramatically upregulated in the retina. However, the role that Cav-1 plays in retinal inflammation has not been studied. We have used our COBRE support for this funding period to test the hypothesis that Cav-1 regulates inflammatory signaling in the retina. Microarray analysis of retinas/eyecups from Cav-1 null mice revealed that, of mRNAs with expression levels 2-fold or higher than controls, a large number are associated with immune responses or inflammatory signaling. The results reflect a shift toward a more pro-inflammatory retinal environment when Cav-1 expression is lost. Furthemore, we discovered a significant increase in the number of bone marrow-derived cells in the retinas of Cav-1 null mice by flow cytometry. Finally, we have found that Cav-1 null retinas display enhanced sensitivity to lipopolysaccharide, a TLR4 ligand. Our results suggest that Cav-1 may play an important role in the maintenance of the retinal immunosuppressive environment. We are now testing the hypothesis that retina-intrinsic expression of Cav-1 mediates this response using our recently generated retina-specific conditional knockout mice. Additional future experiments will determine whether the shift toward pro-inflammatory retinal environment is mediated by TLR signaling.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 最新的眼外证据表明，膜结构域蛋白小窝蛋白-1(Cav-1)通过调节Toll样受体(TLR)信号调节炎症反应和先天免疫。在自身免疫性葡萄膜炎和糖尿病视网膜病变中，视网膜炎症反应强烈，Cav-1在视网膜中的表达显著上调。然而，Cav-1在视网膜炎症中的作用尚未被研究。我们利用我们对这一资助期的Cobre支持来测试Cav-1调节视网膜炎症信号的假设。对Cav-1基因缺失小鼠视网膜/眼球组织的微阵列分析显示，在表达水平为对照组2倍或更高的mRNAs中，有大量与免疫反应或炎症信号有关。这些结果反映了当Cav-1表达缺失时，视网膜环境向更具炎症性的转变。此外，我们还发现CAV-1基因缺失小鼠视网膜中的骨髓源性细胞数量显著增加。最后，我们发现Cav-1缺失的视网膜对TLR4配体脂多糖的敏感性增强。我们的结果提示，Cav-1可能在维持视网膜免疫抑制环境中发挥重要作用。我们现在正在使用我们最近产生的视网膜特异性条件性基因敲除小鼠来验证这一假设，即视网膜固有的Cav-1表达介导了这一反应。未来的更多实验将确定向促炎视网膜环境的转变是否由TLR信号介导。