Retinoic Acid in Development of CNS Vasculature

项目摘要 中枢神经系统（CNS）的血管系统，就像组织一样，是真正独特的。鲜明 CNS血管系统的特征，包括异常密集的血管丛和屏障特性， 在发育过程中由神经环境产生的生物活性配体的混合物刺激。在这 这样，中枢神经系统建立了一个血管丛，以满足其需要。尽管最近的进展，许多神经血管线索， 以及内皮细胞如何整合多种神经源性信号以确保血管 增长和完整性没有得到很好的理解。解决我们知识中的这些差距将使我们深入了解 发育神经血管病变的根本原因，并可能揭示新的治疗 因此，我们需要采取措施来纠正这些缺陷，并防止对CNS造成不可逆的损害。更深入地了解 神经血管发育的基本机制可以为靶向再生和 成熟CNS中的病理性血管生成。 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信号突变体的分析，我们假设RA确保成功的CNS血管 通过调节Wnt-β-catenin信号传导来促进生长、成熟和稳定。我们将测试这个假设， 三个不同的目标。在目标1中，我们将1）确定RA信号在控制脑内皮细胞中的作用， 血管稳定性所需的周细胞增殖和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Sox 17， 由内皮RA和Wnt-β-catenin信号调节，调节CNS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RA在视网膜血管发育中的作用。 早产儿视网膜病变血管病理发育中的RA缺乏完成实验 这项建议将提供有关神经血管发育的分子调节的新知识， 大大增加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 用于开发关于神经血管病变如何发展的新假设，并最终可以 治疗。

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.