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Targeting the inflammatory response in age-related macular degeneration

针对年龄相关性黄斑变性的炎症反应

基本信息

批准号：
10504138
负责人：
Brian P Hafler
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504138
关键词：
Address Age related macular degeneration Atlases Autopsy Blindness Candidate Disease Gene Cell Nucleus Cells Choroidal Neovascularization Chronic Data Deposition Development Disease Disease Progression Drusen Elderly Excision Exudative age-related macular degeneration Eye Fluorescence-Activated Cell Sorting Foundations Future Gene Expression Gene Expression Profile Gene Expression Profiling Generations Genes Genetic Goals Human Immune Immune Targeting Immunohistochemistry In Situ Hybridization Individual Inflammation Inflammatory Inflammatory Response Injections Interleukin-1 Interleukin-1 beta Interleukin-10 Interleukin-17 Interleukins Investigation Knowledge Lead Lesion Lipids Mediating Microglia Modeling Molecular Molecular Profiling Muller&apos s cell Mus Nerve Degeneration Neuroglia Neurons Outcome Pathogenesis Pathogenicity Pathologic Pathologic Neovascularization Pathology Pathway interactions Patients Phenotype Photoreceptors Play Production Proteins Quality of life Research Retina Retinal Degeneration Risk Role Services Signal Pathway Signal Transduction Signaling Molecule System Techniques Transcription Alteration Treatment Efficacy Up-Regulation Vascular Endothelial Growth Factors Work angiogenesis base blood vessel development cell type cytokine drug discovery extracellular genetic signature human tissue immune checkpoint improved insight macrophage matrigel monocyte neovascularization neuroinflammation neuron loss new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics prevent single cell analysis single cell technology single-cell RNA sequencing therapeutic target therapeutically effective transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

新生血管性年龄相关性黄斑变性（AMD）是一种神经炎性疾病