Retinoic Acid in Development of CNS Vasculature

视黄酸在中枢神经系统脉管系统发育中的作用

基本信息

批准号：
9295069
负责人：
Julie Siegenthaler
金额：
$ 32.89万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295069
关键词：
Address Animal Model Biology Blood Blood Circulation Blood Vessels Blood flow Brain Caliber Central Nervous System Diseases Central Nervous System Neoplasms Cerebrovascular system Cues Data Defect Development Disease Endothelial Cells Ensure Environment Genes Genetic Models Goals Growth Human Impaired cognition Injury Knowledge Ligands Link Mediator of activation protein Metabolic Modeling Molecular Motor Mus Neuraxis Neurons Nutrient Oxygen Pathologic Neovascularization Pathology Pathway interactions Pericytes Phenotype Property Recovery Recruitment Activity Regulation Retinal Retinopathy of Prematurity Risk Role SOX17 gene Sensory Signal Pathway Signal Transduction Systems Development Testing Time Tissues Tretinoin Vascular System Vitamin A Vitamin A Deficiency Vitamin Deficiency WNT Signaling Pathway Work angiogenesis base beta catenin brain endothelial cell central nervous system injury density experimental study fetal improved insight mind control mutant neurovascular novel novel therapeutics overexpression prevent rapid growth receptor regenerative relating to nervous system retinal angiogenesis retinoic acid receptor alpha tool transcription factor

项目摘要

Project Summary Central nervous system (CNS) vasculature, like the tissue is supplies, is truly unique. The distinctive features of the CNS vasculature, including an unusually dense vascular plexus and barrier properties, are stimulated during development by a mixture of bioactive ligands produced by the neural environment. In this way, the CNS builds a vascular plexus to fit its needs. Despite recent advances, many neuro-vascular cues likely remain unidentified and how endothelial cells integrate diverse neural-derived signals to ensure vascular growth and integrity is not well understood. Addressing these gaps in our knowledge will provide insight into the underlying causes of developmental neuro-vascular pathologies and potentially reveal novel therapeutic strategies to correct these defects and prevent irreversible damage to the CNS. Further, greater insight into basic mechanisms of neuro-vascular development could offer new tactics to target regenerative and pathological angiogenesis in the mature CNS. We have identified a novel role for Retinoic Acid (RA) signaling in CNS vascular development. Based on our analysis of endothelial RA signaling mutants, we hypothesize that RA ensures successful CNS vessel growth, maturation and stabilization by modulating Wnt-β-catenin signaling. We will test this hypothesis in three distinct aims. In Aim 1, we will 1) identify a role for RA signaling in controlling brain endothelial cell and pericyte proliferation required for vascular stability and 2) determine how RA, via its receptor RARα, inhibits Wnt-β-catenin activity in CNS endothelial cells. In Aim 2, we will determine how transcription factor Sox17, regulated by endothelial RA and Wnt-β-catenin signaling, regulates CNS vascular growth and brain pericyte recruitment. In Aim 3 we will elucidate the function of RA in retinal vascular development and identify a role for RA deficiency in the developmental vascular pathology retinopathy-of-prematurity. Completion of experiments in this proposal will provide new knowledge about molecular regulation of neurovascular development and will add greatly to the working model of CNS endothelial-pericyte regulation, an important framework that can be used to develop new hypothesis regarding how neurovascular pathologies develop and can ultimately be treated.

项目概要中枢神经系统 (CNS) 脉管系统与组织供应品一样，确实是独一无二的。中枢神经系统脉管系统的特征，包括异常密集的血管丛和屏障特性在发育过程中受到神经环境产生的生物活性配体混合物的刺激。尽管最近取得了进展，但中枢神经系统仍会构建血管丛来满足其需要。可能仍然未知，以及内皮细胞如何整合不同的神经源信号以确保血管增长和诚信尚未得到很好的理解，解决我们知识中的这些差距将有助于深入了解。发育性神经血管病理的根本原因并可能揭示新的治疗方法纠正这些缺陷并防止对中枢神经系统造成不可逆转损害的策略进一步深入了解。神经血管发育的基本机制可以提供针对再生和治疗的新策略成熟中枢神经系统中的病理性血管生成。我们已经确定了视黄酸（RA）信号在中枢神经系统血管发育中的新作用。我们对内皮 RA 信号突变体的分析发现，RA 确保了中枢神经系统血管的成功我们将通过调节 Wnt-β-catenin 信号传导来验证这一假设。在目标 1 中，我们将 1) 确定 RA 信号传导在控制脑内皮细胞和血管稳定性所需的周细胞增殖，2) 确定 RA 如何通过其受体 RARα 抑制 CNS 内皮细胞中的 Wnt-β-连环蛋白活性在目标 2 中，我们将确定转录因子 Sox17 的作用。受内皮 RA 和 Wnt-β-catenin 信号传导调节，调节 CNS 血管生长和脑周细胞在目标 3 中，我们将阐明 RA 在视网膜血管发育中的功能，并确定 RA 的作用。发育性血管病理学早产儿视网膜病中的 RA 缺陷完成实验。该提案将提供有关神经血管发育的分子调节的新知识，并将极大地增强了中枢神经系统内皮-周细胞调节的工作模型，这是一个重要的框架，可以用于提出关于神经血管病理如何发展并最终可以被治愈的新假设治疗。