Targeting the inflammatory response in age-related macular degeneration

新生血管性年龄相关性黄斑变性（AMD）是一种神经炎性疾病， 老年人失明的主要原因。虽然AMD中光感受器的参与 我们的研究将研究炎症在炎症中所起的不太为人所知的作用， AMD的发展。我们的建议将解决这一知识差距，并产生详细的 了解炎症相关的AMD发病机制在人类，除了 鉴定AMD的潜在治疗靶点和治疗。我们获取人体组织的途径 来自耶鲁快速尸检服务中心的晚期新生血管性AMD患者和单细胞RNA 测序专业知识将使我们能够进行研究，分析转录组在激活 先天免疫细胞我们的初步数据表明，关键的炎症途径存在于 在小胶质细胞和单核细胞衍生的巨噬细胞中。我们的首要假设是， 先天系统的变化影响AMD的新血管形成，这些变化可能是 旨在阻止疾病进展。为了探索这一假设，我们提出以下两个 具体目标。在目标1中，我们将进行高度平行的单核转录谱分析， 一种新的从患有渗出性AMD的人眼中富集胶质细胞的技术。主要目标是 来定义和询问小胶质细胞和巨噬细胞的分子特征。我们的初步 数据显示，AMD中的小胶质细胞活化并分泌促炎细胞因子 白细胞介素-1b。我们假设炎症分子上调， 与AMD中脉络膜新生血管形成相关。在目标2中，我们将针对亲- 调节AMD中反应性Müller胶质细胞活化的炎性细胞因子，以确定靶向 逆转慢性炎症的途径。根据初步数据，我们的目标 将包括IL-1b、IL-10和IL-17途径以及目标1中确定的其他途径。我们 假设炎症分子对于稳态Müller的转化至关重要， 神经胶质细胞转化为AMD中的反应性促血管生成状态。研究计划将提供 对AMD进展的分子机制的前所未有的深入了解， 有潜力为药物发现确定新的治疗靶点。我们预计，我们的工作将 导致了第一个有效的针对炎症的治疗方法的发展， 从而改善患有新生血管性AMD的个体的生活质量。

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.