Regulation of CNS angiogenesis and barriergenesis

血脑屏障（BBB）在中枢神经系统（CNS）疾病中起着至关重要的作用。功能障碍 BBB常见于几种神经系统疾病，包括中风、癫痫、阿尔茨海默病和脑血管病。 肿瘤，其中脑内皮细胞（BEC）失去屏障特性，获得开窗，并增加 磁导率值得注意的是，血脑屏障阻止了许多治疗剂的自由交换， 这是治疗许多神经系统疾病的挑战性问题。相反，当BBB受损时， 在诸如神经变性病症、脑肿瘤、中风和多发性硬化症的疾病中，炎性 这些病症通常导致外周免疫细胞的浸润，从而促成疾病的病理学。 因此，对血脑屏障形成的基本理解对于提供治疗性见解是至关重要的。 这些疾病。在血脑屏障的发展过程中，CNS血管生成和 屏障形成（即获得BBB特性）。虽然这两个过程都依赖于内部的信号， 发展中的中枢神经系统，驱动血脑屏障形成的精确分子和细胞机制才刚刚开始 有待阐明。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）鉴定了脑血管缺陷的斑马鱼突变体; 2）证明了经典的Wnt信号转导 在缺乏VEGF信号传导的情况下足以形成屏障; 3）确定激活的经典Wnt 神经前体细胞中的信号传导抑制CNS血管生成;和4）鉴定的调节元件， 抑制BEC中的开窗。基于我们令人信服的初步研究，我们的中心假设是， 典型的Wnt信号传导调节VEGF信号传导和使用两种细胞的BEC中屏障特性的获得。 自治和小区非自治机制。我们的具体目标将测试以下假设：（目标 1)经典的Wnt信号调节BEC中的细胞自主VEGF信号，但是VEGF信号可以驱动BEC中的细胞自主VEGF信号。 在缺乏经典Wnt信号传导的情况下CNS血管生成;（目的2）在神经细胞中激活经典Wnt信号传导。 祖细胞抑制血脑屏障的发展;和（目的3）plvap启动子内的调节元件 抑制BEC中的开窗，但不抑制外周内皮细胞。我们建议的研究建立一个 创新的方法来发现新的见解的分子和细胞机制，调节中枢神经系统 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， 允许治疗剂受控进入CNS并修复受损或功能障碍的屏障 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.