The roles and mechanisms of GABA receptor activation in regulating neurogenesis i

GABA受体激活在调节神经发生中的作用和机制

• 批准号: 7790926
• 负责人: Shaoyu Ge
• 金额: $ 29.57万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790926
• 关键词: Adult; Area; Axon; Brain; Brain Diseases; Butyric Acids; Cells; Classification; Confocal Microscopy; Data; Degenerative Disorder; Dendrites; Development; Electron Microscopy; Electrophysiology (science); Embryo; Embryonic Development; Engineering; Epilepsy; Etiology; Generations; Glutamates; Hippocampus (Brain); Image; Immunohistochemistry; Label; Laboratories; Lead; Life; Light; Mammals; Mental disorders; Molecular; Mus; Nature; Neuraxis; Neuronal Differentiation; Neurons; Neurotransmitters; Newborn Infant; Pathology; Physiological; Play; Process; Receptor Activation; Retroviridae; Role; Series; Staging; Stem cells; Synapses; Techniques; adult neurogenesis; combinatorial; dentate gyrus; embryonic stem cell; gamma-Aminobutyric Acid; granule cell; in vivo; migration; nerve stem cell; nervous system disorder; neural precursor cell; neurodevelopment; neurogenesis; neuron development; newborn neuron; novel; novel therapeutics; progenitor; public health relevance; receptor; synaptogenesis; therapy development; two-photon

DESCRIPTION (provided by applicant): Neurogenesis was traditionally believed to occur only during embryonic development in mammals. Only recently has it become generally accepted that new neurons are indeed continuously produced and integrated in discrete regions of the adult mammalian central nervous system. Adult neurogenesis recapitulates the complete process of the neuronal development, from fate specification of neural progenitors, migration, synaptic integration and maturation of newborn dentate granule cells (DGCs). The molecular mechanisms that regulate these neurogenesis steps are largely unknown. Gamma-amino butyric acid (GABA), one of the major inhibitory neurotransmitters in the adult central nervous system, activates GABA receptors in the tonic/phasic mechanisms. Emerging evidence suggests that GABA receptor activity also plays an essential role in regulating the adult neurogenesis. The specific contribution of tonic and/or phasic GABA activation to the proliferation and differentiation of adult neural progenitors and the synaptic integration of their progeny, however, is unknown, and will be examined in our current proposal. Specific Aim I: To determine the roles of tonic GABA receptor activation in regulating proliferation and fate specification of neural progenitors in the adult brain. Specific Aim II: To examine the specific roles of tonic and/or phasic GABA receptor activation in synapse formation and maturation of newborn DGCs in the adult brain. Specific Aim III: To determine the roles of GABA receptor activation in the formation of functional synapses by the axons of newborn DGCs in the adult brain. The approach will be to use engineered retroviruses to genetically manipulate GABAergic activity of the adult neural progenitors and their progeny. The proliferation and differentiation of these genetically-manipulated adult neural progenitors and the synaptic integration of these newborn neurons will be examined. Understanding these regulatory mechanisms for adult neurogenesis may provide clues into the etiology and pathology of these brain disorders and diseases. More importantly, these studies may shed light on novel therapy development such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells. PUBLIC HEALTH RELEVANCE: The adult brain is capable of generating new neurons throughout adulthood. These newborn neurons in the adult brain can successfully integrate into the adult brain. However, we have yet to understand how these new neurons are generated and how these neurons can make the right connections with the existing neurons in the brain. The development of these new neurons shares similar mechanisms with embryonic neuronal development, in which the neurotransmitter, gamma-amino butyric acid (GABA) plays an important role. We propose to decipher the mechanisms of GABA receptor activation in regulating adult neurogenesis. Understanding the kind of factors regulating the generation of these new neurons may provide clues into the etiology and pathology of the brain disorders and diseases. Our studies may potentially lead to the development of novel therapy such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells.

描述（由申请人提供）：传统上认为神经发生仅在哺乳动物的胚胎发育中发生。直到最近，人们普遍认为，新的神经元确实是在成年哺乳动物中枢神经系统的离散区域连续产生和整合的。成人神经发生从神经祖细胞的命运规范，迁移，突触整合和新生儿齿状牙齿颗粒细胞（DGC）的成熟中概述了神经元发育的完整过程。调节这些神经发生步骤的分子机制在很大程度上未知。 γ-氨基丁酸（GABA）是成人中枢神经系统中主要的抑制性神经递质之一，它激活了补品/体质机制中的GABA受体。新兴的证据表明，GABA受体活性在调节成人神经发生中也起着至关重要的作用。然而，滋补和/或阶段性GABA激活对成年神经祖细胞的增殖和分化以及其后代的突触整合的特定贡献是未知的，并且将在我们当前的建议中进行检查。特定目的I：确定补他的GABA受体激活在调节成人大脑中神经祖细胞增殖和命运规范中的作用。特定目标II：检查成人大脑中新生儿DGC的突触形成和新生儿DGC的成熟中的补品和/或阶段性GABA受体激活的特定作用。特定目标III：确定GABA受体激活在成年大脑中新生儿DGC轴突形成功能突触中的作用。该方法是使用工程逆转录病毒来操纵成年神经祖细胞及其后代的GABA能活性。这些遗传操纵的成年神经祖细胞的增殖和分化以及这些新生神经元的突触整合。了解成人神经发生的这些调节机制可能会为这些脑部疾病和疾病的病因和病理学提供线索。更重要的是，这些研究可能会阐明新的治疗发展，例如利用包括胚胎干细胞和成年神经干细胞在内的干细胞的退化神经系统疾病中受损神经元的功能替代。 公共卫生相关性：成年大脑能够在整个成年期产生新的神经元。成人大脑中的这些新生神经元可以成功整合到成人大脑中。但是，我们尚未了解如何产生这些新神经元，以及这些神经元如何与大脑中现有的神经元建立正确的联系。这些新神经元的发展具有相似的机制，具有胚胎神经元发育，其中神经递质γ-氨基丁酸（GABA）起着重要作用。我们建议在调节成人神经发生中破译GABA受体激活的机制。了解调节这些新神经元产生的因素可能为脑部疾病和疾病的病因和病理学提供线索。我们的研究可能会导致新疗法的发展，例如利用包括胚胎干细胞和成年神经干细胞在内的干细胞的退化神经系统疾病中受损神经元的功能替代。