A new class of wet AMD therapeutics

摘要 晚期新生血管性老年性黄斑变性(AMD)以脉络膜为特征 新生血管(CNV)：起源于脉络膜的新生血管侵入黄斑。CNV原因 如果不治疗，永久性中心性失明是AMD最威胁视力的病理。现在 应用程序将调查一类新的CNV疗法的有效性和调节机制。我们 已经在我们的初步数据中确定了酮小体抑制CNV，并假设这种效应是 受巨噬细胞和/或小胶质细胞重新编程调节，导致保护性炎症和/或 抑制病理性炎症。我们将在三个具体目标上驳斥或验证这一假设。在……里面 目的1，我们将确定酮代谢产物的治疗效果及其潜在的协同作用 抗血管内皮生长因子治疗，目前CNV的护理标准。我们还将确定抗血管生成药物是否 酮代谢产物对内皮细胞或酮诱导的免疫细胞的直接作用 使用共培养模型的表型变化。在目标2中，我们将确定酮小体是否抑制CNV 通过小胶质细胞，巨噬细胞从循环中招募，或两者兼而有之。在目标3中，我们将确定 酮体受体，G蛋白偶联受体109a(Gpr109a)在特异性表型重编程中的作用 免疫细胞亚群。

ABSTRACT Advanced neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV), in which neovessels originating from the choroid invade the macula. CNV causes permanent central blindness if left untreated and is the most sight-threatening pathology of AMD. The present application will investigate the efficacy and regulatory mechanisms for a new class of CNV therapeutics. We have identified in our preliminary data that ketone bodies suppress CNV and hypothesize that this effect is regulated by macrophage and/or microglia reprogramming, which results in protective inflammation and/or suppression of pathological inflammation. We will refute or validate this hypothesis in three Specific Aims. In Aim 1, we will determine the therapeutic effects of ketone metabolites and their potential synergistic effect with anti-VEGF therapies, the current standard of care for CNV. We will also determine whether the anti-angiogenic effects of ketone metabolites are regulated by direct effects on endothelial cells or ketone-induced immune cell phenotypic changes using co-culture models. In Aim 2, we will identify whether ketone bodies suppress CNV via microglia, macrophages recruited from the circulation, or both. In Aim 3, we will determine the role of the ketone body receptor, G Protein-coupled receptor 109a (Gpr109a) in phenotypic reprogramming of specific immune cell subpopulations.