Novel Autonomous Roles of CNS Angiogenesis

中枢神经系统血管生成的新自主作用

• 批准号: 9751412
• 负责人: Anju Vasudevan
• 金额: $ 33.4万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751412
• 关键词: Adopted; Adult; Affect; Anatomy; Angiogenesis Pathway; Anxiety; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Symptoms; Blood Vessels; Blood flow; Brain; Categories; Cell Therapy; Cell surface; Cells; Cerebral cortex; Cerebrum; Characteristics; Complex; Cues; Defect; Development; Disease; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Epilepsy; Equilibrium; Etiology; GAD65 enzyme; GAD67 enzyme; Gene Expression; Gene Expression Profile; Genes; Glutamates; Growth; Human; Impairment; In Vitro; Interneurons; Knock-out; Knowledge; Location; Mental Depression; Mental Health; Mental disorders; Metabolic; Midbrain structure; Molecular; Mus; Natural regeneration; Neuraxis; Neurons; Outcome; Pathogenesis; Pathway interactions; Pattern; Population; Positioning Attribute; Process; Prosencephalon; Proteins; Public Health; Radial; Regenerative Medicine; Regulation; Research; Role; Schizophrenia; Shapes; Signal Transduction; Synaptosomes; Telencephalon; Testing; Therapeutic; Transplantation; Vascularization; Ventricular; Work; angiogenesis; autism spectrum disorder; base; brain endothelial cell; brain parenchyma; cell motility; design; developmental disease; effective therapy; falls; gamma-Aminobutyric Acid; genetic approach; histogenesis; in vivo; insight; migration; mouse model; nerve stem cell; nervous system disorder; neurogenesis; neuron development; neuropsychiatric disorder; neuropsychiatry; neurovascular; novel; novel strategies; postnatal; prenatal; prevent; psychiatric symptom; receptor; repaired; vascular abnormality; vesicular GABA transporter

Abstract The central nervous system (CNS) acquires its vasculature by angiogenesis, a process that is critical for its development and repair. Our work has changed notions of cerebral vascularization which implied that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations or treated endothelial cells of the CNS as a homogenous population. Based on origins, anatomical location, independent growth patterns and developmental regulation, forebrain vascular networks fall into two categories: pial and periventricular. The periventricular vascular network that develops in advance of and independent of neuronal development is strategically positioned to provide support and critical guidance cues to instruct neurogenesis and GABAergic interneuron migration in the developing telencephalon. These findings offer new solutions for transplanted primary neuronal precursors that are unable to migrate and integrate into regions requiring new neurons in the absence of proper guidance mechanisms. This application will explore this novel paradigm of neurovascular interactions in diverse ways. It will identify novel angiogenesis mechanisms underlying the origin and etiology of neuropsychiatric diseases. It aims to highlight the novel concept that endothelial GABA signaling is indispensable for brain development shaping postnatal and adult behavior. It attempts to rescue abnormal vascular GABA signaling during embryonic development as a therapeutic approach for long-lasting mental health outcomes. It will examine whether periventricular–like human endothelial cells promote human GABAergic neuronal migration to facilitate development of novel cell based therapies for GABA-related diseases. Results will have far-reaching effects on concepts and mechanisms of regulation of angiogenesis, offer new perspectives on telencephalic histogenesis principles and will lead to discoveries with unprecedented implications for regenerative medicine and treatment of many neurological and psychiatric diseases.

摘要 中枢神经系统（CNS）通过血管生成获得其脉管系统，血管生成是中枢神经系统（CNS）的一个关键过程。 发展和修复。我们的工作改变了脑血管形成的概念， 血管从软脑膜血管丛被动地长入脑实质，以满足代谢的需要。 生长的神经元群体或经处理的CNS内皮细胞作为同质群体。基于 起源，解剖位置，独立生长模式和发育调控，前脑血管 网络分为两类：软脑膜和脑室周围。发育于心脏的室周血管网 神经元发育的进展和独立的战略定位，以提供支持和关键 在发育中的端脑中指导神经发生和GABA能中间神经元迁移的指导线索。 这些发现为移植的不能迁移的原代神经元前体提供了新的解决方案， 在缺乏适当的指导机制的情况下，整合到需要新神经元的区域。本申请 将以不同的方式探索这种神经血管相互作用的新范式。它将识别小说 血管生成机制是神经精神疾病的起源和病因学基础。它的目的是突出 提出了内皮细胞GABA信号传导在脑发育过程中不可或缺的新概念 和成人行为它试图挽救胚胎发育过程中异常的血管GABA信号， 一种长期心理健康结果的治疗方法。它将检查室周样 人内皮细胞促进人GABA能神经元迁移以促进新细胞发育 GABA相关疾病的基础治疗。结果将对概念产生深远影响， 调节血管生成的机制，提供端脑组织发生原则的新观点， 将带来对再生医学和许多疾病治疗具有前所未有影响的发现。 神经和精神疾病。