Novel Developmental Pathways Underlying Psychiatric Disorders

精神疾病背后的新发育途径

基本信息

批准号：
10584586
负责人：
Anju Vasudevan
金额：
$ 53.28万
依托单位：
HUNTINGTON MEDICAL RESEARCH INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584586
关键词：
Adult Affect Anxiety Behavior Behavioral Birth Blood Vessels Blood flow Brain Cells Central Nervous System Cerebral cortex Cerebrovascular system Communication Complex Cues Defect Development Disease Electrophysiology (science)Embryo Endothelial Cells Endothelium Epilepsy Etiology Event GABA Receptor GAD65 enzyme GAD67 enzyme GAT3 transporter Gene Expression Gene Expression Profile Genes Goals Impairment Individual Mediating Mental Depression Mental disorders Microcirculation Midbrain structure Molds Molecular Moods Mus Neocortex Neurons Obsessive-Compulsive Disorder Pathogenesis Pathway interactions Phase Population Positioning Attribute Process Prosencephalon Public Health Regulation Research Role Schizophrenia Shapes Signal Pathway Signal Transduction Time Variant Vascularization Ventricular Work angiogenesis anxiety-related disorders autism spectrum disorder conditional knockout design early embryonic stage gamma-Aminobutyric Acid hindbrain in vivo insight loss of function migration neocortical neuropsychiatric disorder neuropsychiatry neurotransmission neurovascular novel postnatal postnatal development postnatal period prenatal programs receptor repaired vascular factor vesicular GABA transporter vessel regression

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 findings have offered new perspectives on intrinsic regulation of angiogenesis and highlighted the importance of vascular diversity during brain development. Pre-formed vascular networks act as a template for the formation of the neocortex. They are strategically positioned, spatially and temporally to provide support and critical guidance cues to instruct key events of brain development. Recently, our studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling. It revealed that disruptions in endothelial GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders including autism, epilepsy, schizophrenia, anxiety and depression. This vascular GABA signaling pathway extends into the postnatal phase with added complexities. Therefore, our renewal application will examine the key fundamental mechanisms of action of endothelial GABAA receptor-GABA signaling components during the postnatal period with new significance for neocortical development and disease. It aims at highlighting hitherto unknown mechanisms of endothelial GABA’s role in vascular regression and stabilization. It explores the novel concept that endothelial GABA components are indispensable for postnatal brain development and can differentially shape blood flow. Results will uncover fundamental mechanisms governing postnatal angiogenesis, offer new perspectives on the cellular and molecular landscape of the developing neocortex and will lead to discoveries with unprecedented implications for understanding and treatment of several neuropsychiatric illnesses.

抽象的中枢神经系统（CNS）通过血管生成获得其脉管系统，这一过程对其发育和修复至关重要。我们的研究结果为血管生成的内在调节提供了新的视角，并强调了血管多样性在大脑发育过程中的重要性。它们在空间和时间上作为新皮质形成的模板，为指导大脑发育的关键事件提供支持和关键指导线索。独立于神经元 GABA 信号传导的胚胎前脑内皮细胞表明，胚胎早期内皮 GABA 信号传导的破坏可直接导致精神疾病的起源，包括自闭症、癫痫、精神分裂症、焦虑症和抑郁症。因此，我们的更新应用程序将通过新的方法来检查内皮 GABAA 受体 - GABA 信号成分在产后阶段的关键基本作用机制。它旨在强调迄今为止未知的内皮 GABA 在血管退化和稳定中的作用机制。它探索了一个新概念，即内皮 GABA 成分对于出生后大脑发育是必不可少的，并且可以不同地塑造血流。控制出生后血管生成的机制，为发育中的新皮质的细胞和分子景观提供了新的视角，并将导致对理解和治疗几种神经精神疾病具有前所未有的影响的发现。