Regulation of CNS angiogenesis and barriergenesis

血脑屏障(BBB)在中枢神经系统(CNS)疾病中起重要作用。失调症 血脑屏障常见于几种神经疾病，包括中风、癫痫、阿尔茨海默病和大脑 肿瘤，其中脑内皮细胞(BECs)失去屏障特性，获得窗口，并增加 渗透性。值得注意的是，血脑屏障阻止了许多治疗剂的自由交换，呈现出一种 许多神经系统疾病的治疗都是一个极具挑战性的问题。相反，当血脑屏障受损时 在神经退行性疾病、脑肿瘤、中风和多发性硬化症等疾病中，炎性 疾病通常会导致外周免疫细胞的渗透，从而导致疾病的病理。 因此，对血脑屏障形成的基本了解对于为治疗提供治疗见解是必不可少的。 这些疾病。在血脑屏障发育过程中，中枢神经系统血管生成和 障碍产生(即收购BBB财产)。虽然这两个过程都依赖于 发展中的中枢神经系统，驱动血脑屏障形成的确切分子和细胞机制才刚刚开始 有待澄清。我们的总体目标是弥合这方面的知识差距。我们的建议是创新的，因为 我们：1)鉴定出有脑血管缺陷的斑马鱼突变体；2)证明了典型的Wnt信号 足以在缺乏血管内皮生长因子信号的情况下发生屏障；3)确定激活的规范Wnt 神经前体细胞中的信号抑制中枢神经系统血管生成；以及4)确定了可能 抑制BEC的开窗作用。基于我们令人信服的初步研究，我们的中心假设是 规范的Wnt信号调节血管内皮生长因子信号和使用两种细胞的BEC屏障特性的获得 自主和细胞非自主机制。我们的具体目标将检验以下假设：(Aim 1)规范的Wnt信号调节BECs的自主血管内皮生长因子信号，但血管内皮生长因子信号可以驱动 缺乏典型Wnt信号的中枢血管生成；(AIM 2)激活神经中的典型Wnt信号 祖细胞抑制血脑屏障的发育；以及(目标3)plvap启动子内的调节元件 抑制血管内皮细胞开窗，但不抑制外周内皮细胞。我们建议的研究确立了一个 发现调节中枢神经系统的分子和细胞机制的新见解的创新方法 血管生成和屏障形成。我们的长期目标是利用这些信息制定新的战略， 允许治疗剂有控制地进入中枢神经系统，修复受损或功能障碍 与神经系统疾病的病理学有关。

The blood-brain barrier (BBB) plays a vital role in diseases of the central nervous system (CNS). Dysfunction of the BBB is common to several neurological disorders, including stroke, epilepsy, Alzheimer’s disease, and brain tumors, where brain endothelial cells (BECs) lose barrier properties, gain fenestrations, and increase permeability. Significantly, the BBB prevents the free exchange of many therapeutic agents, presenting a challenging problem for the treatment of many neurological diseases. Conversely, when the BBB is compromised in diseases such as neurodegenerative disorders, brain tumors, stroke, and multiple sclerosis, inflammatory conditions often result in the infiltration of peripheral immune cells, contributing to the pathology of the disease. Therefore, a fundamental understanding of BBB formation is essential to provide therapeutic insights into treating these diseases. During BBB development, there is a coordinated effort between CNS angiogenesis and barriergenesis (i.e. the acquisition of BBB properties). While both processes are dependent upon signals within the developing CNS, the precise molecular and cellular mechanisms that drive BBB formation are only beginning to be elucidated. Our overall objective is to bridge the gap in this knowledge. Our proposal is innovative because we: 1) identified zebrafish mutants with defective brain vasculature; 2) demonstrated that canonical Wnt signaling is sufficient for barriergenesis in the absence of Vegf signaling; 3) determined that activated canonical Wnt signaling in neural progenitor cells inhibits CNS angiogenesis; and 4) identified regulatory elements that may suppress fenestrations in BECs. Based upon our compelling preliminary studies, our central hypothesis is that canonical Wnt signaling regulates Vegf signaling and the acquisition of barrier properties in BECs using both cell autonomous and cell non-autonomous mechanisms. Our specific aims will test the following hypotheses: (Aim 1) canonical Wnt signaling regulates cell autonomous Vegf signaling in BECs, but that Vegf signaling can drive CNS angiogenesis in the absence of canonical Wnt signaling; (Aim 2) activated canonical Wnt signaling in neural progenitor cells inhibits the development of the BBB; and (Aim 3) regulatory elements within the plvap promoter suppress fenestrations in BECs, but not peripheral endothelial cells. Our proposed studies establish an innovative approach to discover new insights into the molecular and cellular mechanisms that regulate CNS angiogenesis and barriergenesis. Our long-term goals are to use this information to develop new strategies that permit the controlled access of therapeutic agents into the CNS and repair damaged or dysfunctional barriers associated with the pathology of neurological diseases.