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.

现在很明显，星形胶质细胞（ASTS）具有多种多样的关键功能，可能会影响发展中的和 成熟的大脑。例如，AST的培养和切片制剂表明AST衍生的分子 参与神经元的生存和分化及其突触功能[1-3]。而且， AST衍生的分子可能会影响少突胶质细胞（OLG）谱系细胞的增殖和分化[4-6]。 正在理解控制与AST相关的过程的监管事件。特别是AST 对神经递质的响应，Ca+2的增加，可以以形式传播到相邻的ASTS Ca+2波[7，8]。此外，它们释放神经活性物质，例如谷氨酸，L丝氨酸，D丝氨酸和 影响神经元功能的ATP [9-12]。在最后一个赠款期间，我们发现通过 类似的机制，可能通过合成和释放脑源性神经营养因子影响神经元 （BDNF），一种已知影响神经元存活，分化和突触形成以及OLG的分子 选择性大脑区域的增殖和分化。因此，我们假设ASTS，通过他们的 BDNF的生产和释放在分化中起积极而关键的作用，也许 在发育过程中维持近端神经细胞。探索体内AST的重要性和 进一步定义AST作为BDNF提供商的作用的机制：AIM 1将使用HA-BDNF小鼠 （通过Hempstead进行分析）检查在产后期间BDNF+ AST的发展 bf并确定a）何时在囊泡中存在BDNF，并可以在攻击神经元和OIG中 开发，b）囊泡中BDNF在发育过程和c）的来源如何变化 AST BDNF，无论是内源性还是外源性。 AIM 2将使用有条件删除惊人的淘汰小鼠 他莫昔芬注射时BDNF定义了AST衍生的BDNF对胆碱能神经元和 BF体内产后发育期间的OIG。 AIM 3将确定运输过程 负责调节新合成和内吞的BDNF和分子事件的调节释放 影响这个过程。