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G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature.

G 蛋白偶联受体对视网膜脉管系统转录机制的调节。

基本信息

批准号：
10204421
负责人：
Timothy Tun Hla
金额：
$ 47.53万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10204421
关键词：
Address Adverse effects Age related macular degeneration Anti-Inflammatory Agents Attenuated Blindness Blood Blood Vessels Blood-Retinal Barrier Brain Bulla Cell Culture Techniques Cell Survival Cells Cellular biology Child Childhood Chromatin Code Coupled Development Diabetes Mellitus Diabetic Retinopathy Disease Dose-Limiting Drug Targeting Elderly Endothelial Cells Endothelium Engineering Environment Event Excision Exhibits Exudative age-related macular degeneration Eye FDA approved G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Genetic Genetic Transcription Growth Health Hypertension Hypoxia Impairment Inflammation Inflammatory Response Injury Iron Laboratories Lead Ligands Lipids Maintenance Mediating Metabolic Metabolic stress Modeling Molecular Molecular Chaperones Nutrient Omega-3 Fatty Acids Organ Pathologic Pathology Pathway interactions Patients Pericytes Pharmacology Phase Phenotype Procedures Process Regulation Research Retina Retinal Diseases Retinopathy of Prematurity Role Series Signal Pathway Signal Transduction Sphingosine-1-Phosphate Receptor Spinal Cord TFRC gene Testing Testis Therapeutic Transcription Factor AP-1 Transcriptional Activation Transcriptional Regulation Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Proliferation Vision Visual impairment Work beta catenin cell injury experimental study hand dysfunction inhibitor/antagonist insight lipid mediator loss of function macular edema mouse model multiple sclerosis treatment neonatal mice neuron loss novel premature programs protein expression retina blood vessel structure side effect sphingosine 1-phosphate transcription factor transcriptome transcriptome sequencing transcytosis vascular bed vesicle transport

项目摘要

PROJECT SUMMARY Retinal vascular dysfunction leads to visual impairment and loss of vision, a phenomenon that occurs in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Injury of the retinal endothelial cell (REC) initiates a series of pathogenetic events that ultimately lead to accelerated progression of retinal diseases. How REC injury leads to transcriptional changes that determine whether the retinal vascular function is restored or leads to pathological changes is not known. Sphingosine 1-phosphate (S1P), a blood-borne lipid mediator that signals via G protein-coupled S1P receptors (S1PR1-5). The applicant’s laboratory discovered the first S1PR and worked out its functional roles in vascular barrier maintenance, development/ maturation, anti-inflammatory processes, cell survival and endothelial/ pericyte interactions. Although two FDA-approved S1PR-targeted drugs are efficacious in the treatment of multiple sclerosis, retinal blistering and macular edema are dose-limiting adverse effects due to the impairment of retinal barriers. We recently showed that S1PR signaling suppresses vascular endothelial growth factor (VEGF)-induced AP-1 transcription factor activity and permits Norrin/Wnt/ß-catenin-dependent REC gene expression, thus leading to retinal REC specialization. Among the AP-1 factors, JunB protein expression is most prominently regulated by S1PR signaling, an event needed for optimal vascular network expansion and formation of deep retinal vascular plexus. The central hypothesis of the proposal is that REC S1PR signaling establishes JunB transcription factor gradients and permits the REC organotypic specialization mechanisms. In this manner, attenuated S1PR signaling axis drives poorly functional retinal vascular network and vasoproliferative ROP. In this proposal, the first specific aim will elucidate mechanisms and consequences of S1PR sculpting of JunB transcription factor gradients in REC. Second, how S1PR signaling in the REC promotes organotypic specialization by enabling efficient Norrin/Wnt/ß-catenin-dependent signal transduction and gene expression will be conducted. Specific focus will be on omega-3 fatty acid transporter (MFSD2A) and iron transporter (TFRC). The relevance of these mechanisms in the mouse models of ROP will be addressed in specific aim 3. These studies are anticipated to enhance our understanding of basic mechanisms of retinal vascular development, specialization and disease in the retina and ultimately lead to approaches that tame retinal disorders by targeting the S1P lipid signaling axis and to provide S1PR inhibitors with fewer side effects.

项目总结