Retinoic Acid in Development of CNS Vasculature

项目摘要 中枢神经系统(CNS)的血管系统，就像组织供应一样，确实是独一无二的。与众不同的 中枢神经系统血管系统的特征，包括异常致密的血管丛和屏障特性，是 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。在这 通过这种方式，中枢神经系统建立了一个血管丛来满足它的需要。尽管最近取得了进展，但许多神经血管线索 可能仍未确定，以及内皮细胞如何整合不同的神经衍生信号以确保血管 增长和诚信并没有得到很好的理解。解决我们知识中的这些差距将为我们提供对 发育性神经血管病变的潜在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。此外，更深入地了解 神经血管发育的基本机制可以提供新的策略来靶向再生和 成熟中枢神经系统的病理性血管生成。 我们已经确定了维甲酸(RA)信号在中枢神经系统血管发育中的新作用。基于 我们对内皮RA信号突变的分析，我们假设RA确保CNS血管的成功 通过调节Wnt-β-Catenin信号实现生长、成熟和稳定。我们将在以下方面测试这一假设 三个截然不同的目标。在目标1中，我们将1)确定RA信号在控制脑内皮细胞和 血管稳定性所需的周细胞增殖，以及2)确定RA如何通过其受体RARα抑制 WnT-β-连环蛋白在中枢神经系统内皮细胞的活性。在目标2中，我们将确定转录因子Sox17如何， 受内皮RA和WNT-β-连环蛋白信号调控，调节中枢神经系统血管生长和脑周细胞 招聘。在目标3中，我们将阐明RA在视网膜血管发育中的作用，并确定在 RA缺乏症在早产儿视网膜病理性血管发育中的作用完成实验 将提供有关神经血管发育的分子调控的新知识，并将 大大增加了中枢神经系统内皮细胞-周细胞调节的工作模型，这是一个重要的框架，可以 用来开发关于神经血管病理如何发展以及最终可能 治疗过了。

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.