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Cellular and Molecular Mechanisms of Retinal Fibrosis

视网膜纤维化的细胞和分子机制

基本信息

批准号：
10819024
负责人：
Eric D Nudleman
金额：
$ 42.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10819024
关键词：
Adult Affect Age Applications Grants Area Birth Blindness Blood Vessels Blood-Retinal Barrier Cell secretion Cells Cicatrix Collagen Consensus Contracts Data Deposition Development Diabetic Retinopathy Disease Excision Extravasation Fibroblasts Fibrosis Genetic Goals Histology Hyperoxia Hypoxia Infant Inflammation Integrin alphaV Intervention Ischemia Knockout Mice Left Modeling Molecular Morbidity - disease rate Muller&apos s cell Operative Surgical Procedures Outcome Oxygen Pathologic Pathologic Neovascularization Pathway interactions Patients Pericytes Phase Population Pregnancy Process Recovery Reporting Reproducibility Retina Retinal Diseases Retinopathy of Prematurity Signal Pathway Signal Transduction Smooth Muscle Myocytes Source Structure of retinal pigment epithelium Surface Testing Therapeutic Time Tissues Traction Transforming Growth Factor beta Vascular Diseases Vascular Endothelial Growth Factors Vascular Smooth Muscle Vision Visual cell type conditional knockout effective therapy human disease improved outcome inhibitor mouse model neonatal mice neovascular neovascularization neurosensory novel novel therapeutics postnatal prevent response retinal ischemia single cell sequencing single-cell RNA sequencing

项目摘要

PROJECT ABSTRACT Retinal neovascular disorders, such as retinopathy of prematurity and diabetic retinopathy, are the most common causes of vision loss of working age adults and infants. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders and resulted in improved outcomes for millions of patients worldwide. However, regression of neovascularization often leads to deposition of a fibrotic scar on the surface of the retina. These pre-retinal fibrotic scars can contract, resulting in distortion of the retinal surface or detachment of the neurosensory retina. To date, surgery is the only available intervention, often with poor visual outcomes. Despite the importance, very little is known about the molecular mechanisms that regulate the formation of this pathological tissue, and there is debate on the cellular source of fibrotic scar tissue in the retina. One of the main roadblocks for making progress in this field is the lack of a robust and reproducible mouse model to study and manipulate pre- retinal fibrosis, in order to decipher the key cellular and molecular mechanisms that regulate this process. We have developed a novel mouse model of severe retinopathy of prematurity that develops pre-retinal fibrosis subsequent to hypoxia driven neovascularization. Using histology and single cell sequencing, our preliminary data indicates that the pre-retinal fibrotic scar results from pericytes that upregulate collagen I expression following neovascularization. Here, we propose to further understand the mechanism of pre-retinal scar formation by characterizing and manipulating this novel model. First, we will fully characterize this model examining the time course of fibrotic scar formation, vaso- obliteration, neovascularization, retinal inflammation, and visual function. Second, using lineage tracing and single cell sequencing we will determine the identity the critical collagen I producing cells. Third, we propose to test the hypothesis that activation of TGFβ signaling in pericytes is the key driver of pre- retinal fibrosis. Our goal in understanding the cellular and molecular origin of retinal fibrosis is to develop novel therapeutics to prevent blindness from traction in advanced ischemic retinopathies.

项目摘要