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。

• 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
• 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

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 视网膜血管功能障碍会导致视力损害和视力丧失，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)和新生血管性老年性黄斑变性 (AMD)。视网膜内皮细胞(REC)损伤会引发一系列致病事件，最终导致 导致视网膜疾病加速发展。REC损伤如何导致转录变化，从而决定 视网膜血管功能是否恢复或导致病理改变尚不清楚。鞘氨醇 1-磷酸(S1P)，一种血液传播的脂质介质，通过G蛋白偶联的S1P受体(S1PR1-5)传递信号。 申请人的实验室发现了第一个S1PR，并确定了其在血管屏障中的功能 维持、发育/成熟、抗炎过程、细胞存活和内皮/周细胞 互动。尽管FDA批准的两种S1PR靶向药物在治疗多发性硬化症方面有效 硬化症、视网膜起泡和黄斑水肿是剂量限制的不良反应，这是由于 视网膜屏障。我们最近发现S1PR信号通路抑制血管内皮生长因子 血管内皮生长因子(VEGF)诱导AP-1转录因子活性并允许Norrin/Wnt/？catenin依赖的REC基因 表达，从而导致视网膜REC特化。在AP-1因子中，JunB蛋白的表达是 最重要的是受S1PR信号调节，这是最佳血管网络扩张和 视网膜深血管丛的形成。该提案的中心假设是REC S1PR信号 建立JunB转录因子梯度，并允许REC器官型特化机制。 以这种方式，减弱的S1PR信号轴驱动功能不佳的视网膜血管网络和 血管增生性ROP。在这项提案中，第一个具体目标将阐明 REC中JunB转录因子梯度的S1PR雕刻。第二，REC中的S1PR信令如何 通过有效的Norrin/Wnt/？-catenin依赖的信号转导促进器官类型的特化 并进行基因表达。具体的焦点将是omega-3脂肪酸转运体(MFSD2A)和 铁运输车(TFRC)。这些机制在ROP小鼠模型中的相关性将被解决 这些研究有望加强我们对视网膜基本机制的了解 视网膜中的血管发育、特化和疾病，并最终导致驯服 通过靶向S1P脂质信号轴和提供副作用较少的S1PR抑制剂来治疗视网膜疾病。