The Role of Growth Factors in Brain Development

生长因子在大脑发育中的作用

• 批准号: 8733295
• 负责人: CHERYL F DREYFUS
• 金额: $ 18.15万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733295
• 关键词: Affect; Anticonvulsants; Astrocytes; Biological Models; Brain; Brain region; Brain-Derived Neurotrophic Factor; Calcium; Cells; Development; Electrons; Endocytic Vesicle; Endocytosis; Event; Exocytosis; Female of child bearing age; Foundations; Glial Fibrillary Acidic Protein; Glutamates; Grant; Growth Factor; Growth and Development function; Image; Injection of therapeutic agent; Injury; Instruction; Knockout Mice; Light; Maintenance; Mediating; Mediation; Microscopic; Molecular; Mus; Nervous system structure; Neurons; Neurotransmitters; Oligodendroglia; Pathway interactions; Pharmaceutical Preparations; Play; Positioning Attribute; Preparation; Process; Production; Provider; Role; Serine; Signal Transduction; Slice; Source; Tamoxifen; Transport Process; Valproic Acid; Vesicle; basal forebrain; basal forebrain cholinergic neurons; cholinergic neuron; in vivo; neuronal survival; oligodendrocyte lineage; postnatal; receptor; research study; response; secretogranins; synaptic function; synaptogenesis; therapeutic target; trafficking

It is now clear that astrocytes (asts) have varied and critical functions that may impact the developing and mature brain. For example, culture and slice preparations of asts indicate that ast-derived molecules participate in the survival and differentiation of neurons as well as their synaptic function [1-3]. Moreover, ast-derived molecules may affect proliferation and differentiation of oligodendrocyte (olg) lineage cells [4-6]. The regulatory events that controlthese ast-associated processes are being understood. In particular, asts respond to neurotransmitters with increases in Ca+2 that can be propagated to adjacent asts in the form of Ca+2 waves [7, 8]. Further they release neuroactive substances such as glutamate, L-serine, D-serine and ATP that impact neuron function [9-12]. During the last grant period we found that cultured asts, through a similar mechanism, may impact neurons through synthesis and release of brain-derived neurotrophic factor (BDNF), a molecule known to impact neuronal survival, differentiation and synapse formation as well as olg proliferation and differentiation in selective brain regions. We therefore hypothesize that asts, through their production and release of BDNF play an active and critical role in the differentiation and perhaps maintenance of proximate neural cells during development. To explore the in vivo importance of asts and further define mechanisms underlying the role of asts as BDNF providers: Aim 1 will use HA-BDNF mice (being analyzed by Hempstead) to examine development of BDNF+ asts during the postnatal period in the BF and determine a) when BDNF is present in vesicles and available to impact neurons and oigs during development, b) how the presence of BDNF in vesicles changes during development and c) the source of ast BDNF, whether endogenous or exogenous. Aim 2 will use conditional knockout mice that delete astderived BDNF upon tamoxifen injection to define effects of ast-derived BDNF on cholinergic neurons and oIgs during postnatal development of the BF in vivo. Aim 3 will identify the transport processes that are responsible for regulated release of newly synthesized and endocytosed BDNF and molecular events that impact this process.

现在很清楚，星形胶质细胞（细胞）具有多种关键功能，可能影响发育和发育