Role of Microglia in Retinitis Pigementosa

项目总结/摘要：小胶质细胞是CNS和CNS中的常驻骨髓系细胞。 眼睛和功能的正常组织的维护。视网膜小胶质细胞可以被激活和/或 在疾病期间失调，并因此影响视网膜色素变性的疾病进展。了解 由于缺乏标记物和分子小胶质细胞特征，小胶质细胞的生物学是一个挑战。最近我们 确定了一个稳态分子小胶质细胞的签名，这为研究视网膜病变提供了新的工具。 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。 使用我们的新的小胶质细胞标记物，我们研究了小胶质细胞在rd 1小鼠模型的RP。我们发现 视网膜中常驻小胶质细胞数量增加，但单核细胞无浸润。最重要的是我们 发现玻璃体内转移的小胶质细胞从动物与RP到正常动物，导致感光细胞 损失与此相一致的是，将正常动物的视网膜小胶质细胞玻璃体内转移到患有RP的动物中， 减少光感受器损失。 我们假设在RP中，小胶质细胞增殖并获得细胞毒性表型， 抑制小胶质细胞稳态分子的TREM 2-APOE通路的内在激活 这会导致不受控制的慢性炎症和光感受器损伤。治疗 旨在通过抑制TREM 2-APOE通路靶向小胶质细胞的药物与两种细胞因子的激活有关， TGFβ通路和MERTK消除炎性小胶质细胞表型并恢复视网膜 小胶质细胞的自我平衡特性。这为快速成型技术的研究和新型材料的开发提供了新的方向 针对小胶质细胞的疗法。我们认为，我们的方法的一个创新特点是，它是一种突变- 独立的方法，适用于RP独立的基因突变。此外还有 翻译方面提出的工作，因为我们将调查人眼与我们最近描述的 小胶质细胞抗体。我们将致力于实现以下具体目标： 目标1.确定在小鼠模型和人RP中视网膜小胶质细胞中受影响的分子通路。 目标二。靶向TREM 2-APOE-SPP 1通路以抑制rd小鼠中的MGnD细胞毒性小胶质细胞。 目标3。rd小鼠中通过TGFβ1-MERTK信号转导恢复M0稳态小胶质细胞。

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.