Targeting the inflammatory response in age-related macular degeneration

新生血管性老年性黄斑变性(AMD)是一种神经炎性疾病，是一种 导致老年人失明的主要原因。而光感受器参与AMD 我们的研究已经得到了很好的证实，我们将研究炎症在 AMD的发展。我们的提案将解决这一知识差距，并产生详细的 对人类炎症相关AMD发病机制的了解 AMD潜在治疗靶点和治疗方法的确定。我们获取人体组织的途径 与耶鲁大学快速尸检服务中心的先进新生血管性AMD和单细胞RNA 测序专业技术将使我们能够进行研究，描述激活的转录组 先天免疫细胞。我们的初步数据表明，关键的炎症途径 在小胶质细胞和单核细胞来源的巨噬细胞中。我们最重要的假设是 先天系统的变化影响AMD的新生血管，这些变化可能是 目标是阻止疾病的发展。为了探索这一假设，我们提出了以下两个假设 明确的目标。在目标1中，我们将执行高度并行的单核转录图谱 一种新的渗出型AMD人眼神经胶质细胞富集法。主要目标是 定义和询问小胶质细胞和巨噬细胞的分子特征。我们的预赛 数据显示AMD患者小胶质细胞活化，并分泌促炎细胞因子 白介素1b。我们假设有同样的炎症分子上调，这是 与AMD的脉络膜新生血管相关。在目标2中，我们将针对专业人士- 炎性细胞因子调节AMD中反应性Müller神经胶质细胞的激活以确定靶向 逆转疾病慢性炎症的途径。根据初步数据，我们的目标 将包括IL-1b、IL-10和IL-17途径以及在目标1中确定的其他途径。 假设炎症分子对动态平衡Müler的转变至关重要 在AMD中，胶质细胞向反应性、促血管生成状态转变。拟议的研究计划将提供 对AMD进展的分子机制的前所未有的见解，并具有重要意义 为药物发现确定新的治疗靶点的可能性。我们预计，我们的工作将 导致了针对炎症的第一种有效治疗方法的发展， 从而提高新生血管性AMD患者的生活质量。

Neovascular age-related macular degeneration (AMD) is a neuroinflammatory disease that is a leading cause of blindness in the elderly. While the involvement of photoreceptors in AMD has been well established, our research will study the less understood role that inflammation plays in the development of AMD. Our proposal will address this knowledge gap and yield a detailed understanding of inflammation-associated AMD pathogenesis in humans, in addition to the identification of potential therapeutic targets and treatments for AMD. Our access to human tissue with advanced neovascular AMD from the Yale Rapid Autopsy Service and single-cell RNA sequencing expertise will allow us to perform studies that profile the transcriptome in activated innate immune cells. Our preliminary data indicate that the critical inflammatory pathways reside in microglia and monocyte-derived macrophages. Our overarching hypothesis is that functional changes in the innate system influence neovascularization in AMD, and these changes may be targeted to halt disease progression. To explore this hypothesis, we propose the following two specific aims. In Aim 1, we will perform highly parallel single-nucleus transcriptional profiling with a novel enrichment technique for glia from human eyes with exudative AMD. The primary goal is to define and interrogate the molecular signature of microglia and macrophages. Our preliminary data revealed activated microglia in AMD with secretion of the proinflammatory cytokine interleukin-1b. We hypothesize that there is as upregulation of inflammatory molecules, which is associated with choroidal neovascularization in AMD. In Aim 2, we will target the pro- inflammatory cytokines that regulate activation of reactive Müller glia in AMD to identify targetable pathways to reverse the chronic inflammation in disease. Based on preliminary data, our targets will include the IL-1b, IL-10, and IL-17 pathways as well as additional ones identified in Aim 1. We hypothesize that inflammatory molecules are critical for the transformation of homeostatic Müller glia to a reactive, pro-angiogenic state in AMD. The proposed research plan will provide unprecedented insight into the molecular mechanisms of AMD progression and has significant potential to identify novel therapeutic targets for drug discovery. We anticipate that our work will lead to the development of the first effective therapeutic approaches targeting inflammation, thereby improving the quality of life for individuals suffering from neovascular AMD.