Novel Autonomous Roles of CNS Angiogenesis

中枢神经系统血管生成的新自主作用

基本信息

批准号：
10242957
负责人：
Anju Vasudevan
金额：
$ 33.99万
依托单位：
HUNTINGTON MEDICAL RESEARCH INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242957
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 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 conditional knockout 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 regenerative treatment repaired vascular abnormality vesicular GABA transporter

项目摘要

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.

抽象的中枢神经系统 (CNS) 通过血管生成获得脉管系统，这一过程对于其正常运转至关重要我们的工作改变了脑血管化的概念，这意味着血液。血管从软脑膜血管丛被动地长入脑实质，以满足新陈代谢的需要基于中枢神经系统生长的神经元群体或经过处理的内皮细胞作为同质群体。起源、解剖位置、独立生长模式和发育调节、前脑血管网络分为两类：软脑膜和脑室周围血管网络。神经发育的进步和独立于神经发育的战略定位是提供支持和关键指导发育中端脑神经发生和 GABA 能中间神经元迁移的引导线索。这些发现为无法迁移和迁移的移植原代神经前体提供了新的解决方案在缺乏适当引导机制的情况下整合到需要新神经元的区域中。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新的。神经精神疾病的起源和病因学的血管生成机制旨在强调。内皮 GABA 信号对于出生后大脑发育不可或缺的新概念它试图挽救胚胎发育过程中异常的血管 GABA 信号传导。一种长期心理健康结果的治疗方法它将检查脑室周围是否类似。人内皮细胞促进人 GABA 能神经元迁移，以促进新细胞的发育基于 GABA 相关疾病的治疗结果将对概念和方法产生深远影响。血管生成的调节机制，为端脑组织发生原理提供新的视角将对再生医学和许多疾病的治疗产生前所未有的影响神经和精神疾病。