Mechanisms regulating vessel development in the embryonic and postnatal brain

描述（由申请人提供）：本研究的长期目标是了解神经细胞，特别是各种胶质细胞， 类型调节出生前和出生后的脑血管生成，并协调神经血管单位的发育。适当的血管发育对正常的脑功能至关重要，这一过程中的缺陷与许多神经系统疾病有关，包括中风，癫痫和神经变性。许多调节血管发育的相同途径也调节成人大脑中的血管完整性和功能，并且需要重新激活以用于疾病后的血管恢复。此外，血脑屏障（BBB）是用于疾病治疗的药物向中枢神经系统（CNS）递送的主要障碍。因此，更好地了解脑血管生成和BBB的发展是至关重要的，以找到更好的治疗各种人类疾病。为此，我们建议专注于神经和血管细胞之间的相互作用，因为这些相互作用是负责许多独特的性质的脑血管系统。我们假设神经细胞，特别是胶质细胞在出生前和出生后的脑血管生成中起着关键作用。作为支持，我们的初步数据显示，从胚胎皮层切除神经祖细胞会导致血管退化和脑出血。我们还发现，从出生后早期的大脑神经胶质消融破坏血管网络的制作和成熟。因此，这些研究结果提供了独特的机会，更好地了解分子机制，调节血管发育整个皮质。为此，我们将：1）确定神经细胞调节胚胎脑血管稳定性的信号通路; 2）确定脑内皮细胞调节血管稳定性的细胞内机制; 3）确定神经胶质细胞调节出生后脑中血管发育的信号机制。通过这些努力，我们可能会揭示新的分子机制，通过这些机制调节脑血管生成的不同步骤，为疾病治疗中需要协调重新激活血管恢复的信号通路提供新的见解。我们还将可能实质性地阐明脑内皮细胞调节血管稳定性的基因表达程序，并为相关疾病的药物干预提供潜在的分子靶点。

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand molecular mechanisms of intercellular signaling by which neural cells especially various glial cell types regulate pre- and postnatal brain angiogenesis, and coordinate the development of the neurovascular unit. Proper vascular development is critical to normal brain function and defects in this process are linked to many neurological diseases including stroke, epilepsy, and neurodegeneration. Many of the same pathways that regulate vessel development also regulate vascular integrity and function in the adult brain and need to be re-activated for vascular recovery following disease. In addition, blood brain barrier (BBB) is a major obstacle to central nervous system (CNS) delivery of pharmaceuticals for disease treatment. Thus, a better understanding of brain angiogenesis and BBB development is crucial to finding better treatments for a wide array of human diseases. To this end, we propose to focus on interactions between neural and vascular cells, since these interactions are responsible for many of the unique properties of the brain vasculature. We hypothesize that neural cells especially glia play a key role in both pre- and postnatal brain angiogenesis. In support, our preliminary data show that ablation of neural progenitors from the embryonic cortex results in vessel regression and cerebral hemorrhage. We also find that ablation of glia from the early postnatal brain disrupts vessel network elaboration and maturation. These findings therefore provide unique opportunities for better understanding molecular mechanisms that regulate vessel development throughout corticogenesis. To this end, we will: 1) Determine the signaling pathway(s) by which neural cells regulate embryonic brain vessel stabilization; 2) Determine intracellular mechanisms by which brain endothelial cells regulate vessel stabilization; 3) Determine signaling mechanisms by which glia regulate vessel development in the postnatal brain. Through these efforts, we will likely reveal novel molecular mechanisms by which the distinct steps of brain angiogenesis are regulated, providing new insights into the signaling pathways that need to be coordinately re-activated for vascular recovery in disease treatment. We will also likely substantially elucidate the gene expression program by which brain endothelial cells regulate vessel stabilization, and provide potential molecular targets for pharmaceutical intervention in relevant diseases.