IN VIVO ROLE OF CAVEOLIN-1 IN MODULATING PHOTORECEPTOR FUNCTION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 最近的证据表明，眼外的膜结构域蛋白，小窝蛋白-1（Cav-1）通过调节Toll样受体（TLR）信号转导来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性视网膜病变中，共享强烈视网膜炎症作为病理组分的病症中，Cav-1表达在视网膜中显著上调。然而，Cav-1在视网膜炎症中的作用尚未研究。我们已经使用我们的COBRE支持这个资助期来测试Cav-1调节视网膜炎症信号的假设。对Cav-1缺失小鼠视网膜/眼罩的微阵列分析显示，在表达水平是对照组2倍或更高的mRNA中，大量与免疫反应或炎症信号相关。结果反映了当Cav-1表达丢失时，向更促炎的视网膜环境的转变。此外，我们通过流式细胞术发现Cav-1基因敲除小鼠视网膜中骨髓来源细胞的数量显著增加。最后，我们发现Cav-1缺失的视网膜显示出对脂多糖（一种TLR 4配体）增强的敏感性。我们的研究结果表明，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Cav-1的视网膜内在表达介导这种反应的假设。其他未来的实验将确定向促炎视网膜环境的转变是否由TLR信号传导介导。

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.