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The Membrane Attack Complex and the Choriocapillaris in Health and Age-Related Macular Degeneration

健康和年龄相关性黄斑变性中的膜攻击复合体和脉络膜毛细血管

基本信息

批准号：
10432127
负责人：
Andrew P Voigt
金额：
$ 4.07万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2023-05-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432127
关键词：
Adult Affect Age Age related macular degeneration Aging Apoptosis Blindness Blood Vessels Blood capillaries Blood flow Caliber Cell Cycle Cell Death Cell Line Cells Choroid Complement Complement Activation Complement Membrane Attack Complex Data Deposition Development Elderly Endothelial Cells Etiology Event Eye Functional disorder Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Health Human In Vitro Individual Injury Innate Immune System Intervention Lead Link Lytic Mediating Mediator of activation protein Mission Molecular Molecular Target Newborn Infant Outcomes Research Oxygen PECAM1 gene Pathogenesis Photoreceptors Predisposition Proteins RNA Retina Retinal Photoreceptors Role Savings Seminal Structure Structure of retinal pigment epithelium System Testing Tissues United States Validation Vascular Diseases Venous Western World age related arm capillary bed cdc Genes differential expression endothelial dysfunction histological image induced pluripotent stem cell new therapeutic target novel photoreceptor degeneration response single-cell RNA sequencing stem cells transcriptome transcriptomics vascular bed vision development young adult

项目摘要

PROJECT SUMMARY Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the western world. While the etiology of AMD is multifactorial, dysfunction of the choroidal vasculature, which provides the majority of oxygen to retinal photoreceptors, has been implicated as the earliest detectable event in AMD. An important contributor to choroidal vascular dysfunction is complement activation. Complement is a multiprotein component of the innate immune system that results in the formation of a lytic structure known as the membrane attack complex (MAC). While systemic vascular beds remain free from MAC formation, the superficial choroidal capillary system known as the choriocapillaris uniquely accumulates the MAC with advancing age. Such MAC accumulation is proposed to cause lytic injury to choriocapillaris endothelial cells and the downstream sequelae of AMD. However, the mechanisms that lead to choriocapillaris MAC accumulation are widely unknown. We hypothesize that unique transcriptional networks drive choriocapillaris development, which make these endothelial cells particularly susceptible to age-related molecular changes and MAC-mediated cell death. To test this hypothesis, we propose the following three specific aims: 1. Identify molecular features that make the choriocapillaris uniquely susceptible to MAC formation. We will differentiate choriocapillaris, arterial, and venous endothelial cells from human induced pluripotent stem cells and identify transcriptomic drivers of the choriocapillaris cell fate. After single-cell RNA sequencing, we will functionally validate choriocapillaris-enriched genes that influence MAC formation in vitro. 2. Identify molecular changes in age and AMD that increase choriocapillaris MAC accumulation and MAC- mediated damage. We will identify choroidal endothelial cell gene expression differences between young, adult (5th - 6th decade), elderly (8th - 9th decade) and AMD human donors. We will test the degree to which differentially expressed targets in aging choriocapillaris influence formation of the MAC in vitro. 3. Determine the role of RGCC in response to the MAC in health and AMD. We will quantify RGCC, a gene recently identified to be highly expressed in human choriocapillaris and implicated in MAC-mediated endothelial dysfunction, at the RNA and protein level using human choroids from healthy and AMD donors. We will also functionally assess the degree to which RGCC mediates endothelial cell death and dysfunction in both choriocapillaris and non-ocular endothelial cell lines. When successful, these studies will identify novel molecular features that lead to MAC accumulation and choriocapillaris damage. Further understanding how choriocapillaris cells accumulate and respond to the MAC may lead to new therapeutic targets for AMD, supporting the Mission, Goals, and Objectives of the NEI.

项目总结