A new class of wet AMD therapeutics

新型湿性 AMD 疗法

基本信息

批准号：
10659582
负责人：
Elizabeth Moran
金额：
$ 39.13万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659582
关键词：
Ablation Acetates Address Adoptive Transfer Affect Age Age related macular degeneration Angiogenesis Inhibitors Animals Anti-Inflammatory Agents Basic Science Benchmarking Binding Biological Assay Blindness Cadaver Cell Respiration Cell Separation Cells Choroid Choroidal Neovascularization Circulation Clinical Research Coculture Techniques Complication Coupled Data Disease Elderly Endothelial Cells Exudative age-related macular degeneration Eye Flow Cytometry Foundations G-Protein-Coupled Receptors Genes Genetic Polymorphism Glycolysis Immune In Vitro Incidence Infiltration Inflammation Inflammatory Intervention Invaded Ketone Bodies Ketones Ketoses Ketosis Kinetics Knockout Mice Knowledge Lasers Left Legal Blindness Lesion Link Liver Macrophage Metabolic Metabolism Microglia Modeling Natural Immunity Pathologic Pathology Patients Peripheral Phenotype Play Population Process Retina Risk Role Severities Testing Therapeutic Therapeutic Effect Treatment Efficacy VLDL receptor Vision Work angiogenesis beta-Hydroxybutyrate bevacizumab cell type dietary genome wide association study immunoregulation legally blind macula monocyte neovascularization neutrophil oxidized lipid paracrine programs receptor recruit single-cell RNA sequencing standard of care therapy development

项目摘要

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.

抽象的晚期新血管相关的黄斑变性（AMD）的特征是脉络膜新生血管形成（CNV），其中的神经源自脉络膜侵入黄斑。 CNV原因永久性的中央失明如果未经治疗，并且是AMD的视力危及最多的病理学。现在应用将研究新的CNV治疗剂的功效和调节机制。我们在我们的初步数据中已经确定了酮体抑制CNV并假设这种影响是受巨噬细胞和/或小胶质细胞重编程的调节，导致保护性炎症和/或抑制病理炎症。我们将在三个特定目标中反驳或验证这一假设。在 AIM 1，我们将确定酮代谢产物的治疗作用及其潜在的协同作用抗VEGF疗法，当前的CNV护理标准。我们还将确定是否抗血管生成酮代谢产物的影响受到对内皮细胞或酮诱导的免疫细胞的直接影响使用共培养模型的表型变化。在AIM 2中，我们将确定酮体是否抑制CNV 通过小胶质细胞，从循环中募集的巨噬细胞，或两者兼而有之。在AIM 3中，我们将确定酮体受体，G蛋白偶联受体109a（GPR109A）在特定的表型重编程中免疫细胞亚群。