Role of Microglia in Retinitis Pigementosa

项目摘要/摘要：小胶质细胞是驻留在中枢和大脑中的髓系细胞。 眼睛的功能和维持正常组织的功能。视网膜小胶质细胞可被激活和/或 在疾病过程中调节失调，从而影响视网膜色素变性的疾病进展。了解 由于缺乏标记和分子标记，小胶质细胞的生物学研究是一个挑战。最近，我们 发现了一个动态平衡的分子小胶质细胞特征，这为研究视网膜提供了新的工具 小胶质细胞生物学和靶向视网膜小胶质细胞治疗视网膜色素变性的可能性。 使用我们新的小胶质细胞标记物，我们研究了Rd1小鼠RP模型中的小胶质细胞。我们发现 视网膜内驻留的小胶质细胞数量增加，但未见单核细胞渗入。最重要的是，我们 发现视网膜色素变性动物的小胶质细胞在玻璃体内移植到正常动物体内，导致光感受器的产生 损失。与此一致的是，视网膜小胶质细胞从正常动物到RP动物的玻璃体内移植 减少了光感受器的损失。 我们假设，在RP中，小胶质细胞增殖并获得一种细胞毒表型，通过 抑制小胶质细胞内稳分子的TREM2-APOE途径的内在激活 并导致失控的慢性炎症和光感受器损伤。治疗 目的是通过抑制TREM2-APOE通路来靶向小胶质细胞 转化生长因子β途径和MERTK在消除炎性小胶质细胞表型和修复视网膜中的作用 小胶质细胞的动态平衡特性。这为快速原型技术的研究和小说的发展提供了新的方向 以小胶质细胞为靶点的疗法。我们相信，我们方法的一个创新特征是它是一种突变- 独立的方法，适用于不依赖于基因突变的RP。此外，还有一个 翻译方面的拟议工作，因为我们将调查人眼与我们最近描述的 小胶质细胞抗体。我们将解决以下具体目标： 目的1.在小鼠模型和人视网膜色素变性模型中确定视网膜小胶质细胞受影响的分子通路。 目的2.靶向TREM2-APOE-SPP1通路抑制RD小鼠MGnD-细胞毒性小胶质细胞。 目的3.通过转化生长因子β1-MERTK信号通路恢复RD小鼠体内平衡的小胶质细胞。

PROJECT SUMMARY/ABSTRACT: Microglia are resident myeloid-lineage cells in both the CNS and in the eye and function in the maintenance of normal tissue. Retinal microglia can become activated and/or dysregulated during disease, and thus affect disease progression in retinitis pigmentosa. Understanding the biology of microglia is a challenge due to absence of markers and molecular microglia signatures. Recently, we identified a homeostatic molecular microglia signature which provides new tools for investigating retinal microglial biology and the possibility of targeting retinal microglia for the treatment of retinitis pigmentosa. Using our new microglial markers, we investigated microglia in the rd1 murine models of RP. We found increased numbers of resident microglia but no infiltration of monocytes in the retinal. Most importantly, we found that intravitreal transfer of microglia from animals with RP into normal animals, resulted in photoreceptor loss. Consistent with this, intravitreal transfer of retinal microglia from normal animals into animals with RP reduced photoreceptors loss. We hypothesize that in RP, microglia proliferate and acquire a cytotoxic phenotype mediated by intrinsic activation of the TREM2-APOE pathway which suppresses microglia homeostatic molecular properties and leads to uncontrolled chronic inflammation and photoreceptors damage. Treatments aimed to target microglia by suppressing the TREM2-APOE pathway is associated with activation of both the TGFβ pathway and MERTK which abrogates the inflammatory microglial phenotype and restores retinal microglial homeostatic properties. This provides a new direction for studying RP and development of novel therapies that target microglia. We believe that an innovative feature of our approach is that it is a mutation- independent approach that applies to RP independent of the genetic mutation. In addition, there is a translational aspect to the proposed work as we will investigate human eyes with our recently described microglial antibodies. We will address the following specific aims: Aim 1. Identify molecular pathways affected in retinal microglia in mouse models and human RP. Aim 2. Target the TREM2-APOE-SPP1 pathway to inhibit MGnD-cytotoxic microglia in rd mice. Aim 3. Restore M0-homeostatic microglia via TGFβ1-MERTK signaling in rd mice.