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 加速视网膜疾病的进展。 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 互动。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由于视网膜功能受损而导致的剂量限制性不良反应。 视网膜屏障。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 专门化。 AP-1因子中，JunB蛋白表达量为 最显着地受 S1PR 信号传导调节，这是最佳血管网络扩张和 视网膜深部血管丛的形成。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。 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， 血管增生性 ROP。在该提案中，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。二、REC中S1PR信令如何 通过实现高效的 Norrin/Wnt/ß-catenin 依赖性信号转导来促进器官型特化 并进行基因表达。特别关注的是 omega-3 脂肪酸转运蛋白 (MFSD2A) 和 铁转运蛋白（TFRC）。这些机制在 ROP 小鼠模型中的相关性将得到解决 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。