Slit2-ROBO signaling in pericytes and myeloid cells controls vascular development and ocular neovascular disease

周细胞和骨髓细胞中的 Slit2-ROBO 信号控制血管发育和眼部新生血管疾病

基本信息

批准号：
10363427
负责人：
Anne Christine Eichmann
金额：
$ 60.11万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363427
关键词：
Affect Age related macular degeneration American Biological Biology Blindness Blood Vessels Blood-Retinal Barrier Cells Communication Data Development Diabetic Retinopathy Disease Disease Progression Elderly Endothelial Cells Endothelium Gene Expression Growth Factor Inhibition Hemorrhage Homeostasis Human Impairment Inflammation Inflammatory Knowledge Ligands Mediating Molecular Mus Myelogenous Myeloid Cells Pathologic Neovascularization Pathology Pathway interactions Patients Pericytes Receptor Signaling Retina Retinal Neovascularization Retinopathy of Prematurity Role Signal Transduction Therapeutic Therapeutic Agents Treatment Factor Vascular Endothelial Growth Factors Vision Visual angiogenesis base cell motility cell type cytokine disorder prevention interest migration mouse model neovascular neovascularization neurovascular coupling novel novel strategies novel therapeutics ocular neovascularization polypeptide prevent receptor response retinal angiogenesis single-cell RNA sequencing targeted agent

项目摘要

PROJECT SUMMARY Pericytes and myeloid cells cooperate with endothelium to orchestrate formation of a properly branched, functional vessel network that sustains retinal function and thereby enables vision. Disrupted communication between endothelium, pericytes and myeloid cells leads to excessive and pathological angiogenesis in ocular neovascular diseases (ONDs) such as advanced age-related macular degeneration and diabetic retinopathy that cause vision loss in millions of Americans. Excessive angiogenesis is currently treated by inhibition of a single factor VEGF that targets endothelial cells only. In this proposal we identify a novel SLIT2-ROBO1&2 ligand- receptor pathway that promotes retinal neovascularization through direct receptor signaling effects in pericytes and myeloid cells. By targeting pericytes and myeloid cells, ROBO inhibition in ONDs may confer additional benefit over VEGF inhibition of ECs alone. We will define the molecular basis of SLIT2-ROBO1&2 signaling and its biological role in pericytes and myeloid cells to uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention.

项目摘要周细胞和髓样细胞与内皮配合，以编排适当分支的形成维持视网膜功能并因此可以实现视觉的功能血管网络。沟通中断在内皮，周细胞和髓样细胞之间导致眼部过度和病理血管生成新生血管疾病（OND），例如与年龄相关的黄斑变性和糖尿病性视网膜病变导致数百万美国人的视力丧失。目前通过抑制单一来治疗过度的血管生成仅针对内皮细胞的因子VEGF。在此提案中，我们确定了一种新颖的slit2-robo1和2配体 - 受体途径通过周细胞中的直接受体信号效应促进视网膜新血管形成和髓样细胞。通过靶向周细胞和髓样细胞，OND中的机器人抑制可能会赋予更多仅利用VEGF抑制EC的利益。我们将定义SLIT2-ROBO1和2信号传导的分子基础它在周细胞和髓样细胞中的生物学作用，以发现控制视网膜发育和可以应用于预防OND的稳态。