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.

项目摘要视网膜血管功能障碍会导致视觉障碍和视力丧失，这种现象发生在早产视网膜病变（ROP），糖尿病性视网膜病（DR）和新血管相关的黄斑变性（AMD）。视网膜内皮细胞（REC）的损伤引发了一系列的致病事件，这些事件最终导致加速残留疾病的进展。 rec损伤如何导致转录变化确定尚不清楚视网膜血管功能是否恢复或导致病理变化。鞘氨醇 1-磷酸盐（S1P），一种通过G蛋白偶联的S1P受体（S1PR1-5）发出信号的血源脂质介质。申请人的实验室发现了第一个S1PR，并在血管屏障中扮演了功能角色维护，发育/成熟，抗炎过程，细胞存活和内皮/周细胞互动。尽管两种FDA批准的S1PR靶向药物在处理多个方面有效由于损害视网膜屏障。我们最近表明，S1PR信号抑制了血管内皮生长因子（VEGF）诱导的AP-1转录因子活性并允许Norrin/Wnt/ß-catenin依赖性REC基因表达，从而导致视网膜恢复专业化。在AP-1因子中，JUNB蛋白的表达是最大程度地受到S1PR信号的调节，最佳血管网络扩展所需的事件和深视网膜血管丛的形成。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器官专业化机制。以这种方式，减弱的S1PR信号轴驱动功能较差的永久性血管网络和血管增生ROP。在此提案中，第一个具体目标将阐明机制和后果 rec中JUNB转录因子梯度的S1PR雕刻。第二，REC中的S1PR信号如何通过启用有效的Norrin/Wnt/ß-catenin依赖性信号转移来促进有机专业化并将进行基因表达。具体的重点将放在omega-3脂肪酸转运蛋白（MFSD2A）和铁转运蛋白（TFRC）。这些机制在ROP的鼠标模型中的相关性将被解决在特定的目标3中。预计这些研究将增强我们对残留基本机制的理解视网膜中的血管发展，专业化和疾病，并最终导致驯服通过靶向S1P脂质信号轴并为S1PR抑制剂提供更少的副作用来通过视网膜疾病。