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：
10596099
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/10596099
关键词：
Acceleration 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 Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Gene Deletion 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 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 inhibitor insight lipid mediator loss of function macular edema mouse model multiple sclerosis treatment neonatal mice neuron loss novel permissiveness pharmacologic 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.

项目概要视网膜血管功能障碍导致视力障碍和视力丧失，这种现象发生在早产儿视网膜病变 (ROP)、糖尿病视网膜病变 (DR) 和新生血管性年龄相关性黄斑变性 (AMD) 视网膜内皮细胞 (REC) 损伤引发一系列致病事件，最终导致。 REC 损伤如何导致转录变化，从而加速视网膜疾病的进展。鞘氨醇是否使视网膜血管功能恢复或导致病理变化尚不清楚。 1-磷酸 (S1P)，一种血源性脂质介质，通过 G 蛋白偶联 S1P 受体 (S1PR1-5) 发出信号。申请人的实验室发现了第一个S1PR并阐明了其在血管屏障中的功能作用维持、发育/成熟、抗炎过程、细胞存活和内皮/周细胞尽管 FDA 批准的两种 S1PR 靶向药物可有效治疗多种疾病。硬化、视网膜起泡和黄斑水肿是剂量限制性效应，由于我们最近发现 S1PR 信号传导抑制血管内皮生长因子。 (VEGF) 诱导 AP-1 转录因子活性并允许 Norrin/Wnt/ß-连环蛋白依赖性 REC 基因表达，从而导致视网膜 REC 特化在 AP-1 因子中，JunB 蛋白表达最高。最显着地受 S1PR 信号传导调节，这是最佳血管网络扩张和该提案的中心假设是 REC S1PR 信号传导。建立 JunB 转录因子梯度并允许 REC 器官型特化机制。通过这种方式，减弱的 S1PR 信号轴会驱动功能较差的视网膜血管网络，在本提案中，第一个具体目标将阐明血管增殖性 ROP 的机制和后果。 REC 中 JunB 转录因子梯度的 S1PR 塑造其次，REC 中的 S1PR 信号传导如何。通过实现高效的 Norrin/Wnt/ß-连环蛋白依赖性信号转导来促进器官型特化并将特别关注 omega-3 脂肪酸转运蛋白 (MFSD2A) 和基因表达。将讨论这些机制在 ROP 小鼠模型中的相关性。具体目标3。预计这些研究将增强我们对视网膜基本机制的理解视网膜的血管发育、特化和疾病，并最终导致驯服的方法通过靶向 S1P 脂质信号轴来治疗视网膜疾病，并提供副作用更少的 S1PR 抑制剂。