Glial Modulation of Cortical Development and Drug of Abuse-induced Brain Damage

胶质细胞对皮层发育的调节和药物滥用引起的脑损伤

基本信息

批准号：
7740482
负责人：
Dong Feng Chen
金额：
$ 28.88万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7740482
关键词：
Affect Age Area Astrocytes Attenuated Binding Biological Process Birth Brain Brain Injuries Brain region Cell Culture System Cell Culture Techniques Cells Cerebrum Chickens Cocaine Cognitive Cortical Malformation Data Defect Development Drug Addiction Drug abuse Event Exhibits FGFR4 gene Family Fetal Growth Fetus Fibroblast Growth Factor Future Genes Glial Differentiation Goals Homologous Gene Human Immunohistochemistry In Situ In Situ Hybridization In Vitro Knockout Mice Laboratories Lead Life Mediating Mental disorders Messenger RNA Molecular Mothers Multipotent Stem Cells Mus Nerve Degeneration Neuraxis Neurobiology Neuroglia Neurons Oligodendroglia Pathogenesis Pathway interactions Pattern Perinatal Exposure Pharmaceutical Preparations Play Prefrontal Cortex Process Production Prosencephalon Regulation Reporting Research Role Signal Pathway Signal Transduction Signaling Molecule Stem cells Testing Therapeutic Therapeutic Intervention Time Undifferentiated Wild Type Mouse axon guidance brain malformation cell growth cell type cellular targeting cocaine exposure combat design developmental disease drug development drug of abuse fetal fibroblast growth factor receptor 4 frontal lobe gain of function glial cell development gliogenesis in vivo insight loss of function malformation member migration mouse fibroblast growth factor 15 neocortical nerve stem cell nervous system development nervous system disorder neurodevelopment neurogenesis neuroregulation pregnant premature public health relevance relating to nervous system research study scaffold synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Neurons and glial cells arise sequentially from common progenitor cells during vertebrate CNS development. The mechanism that governs the transition of progenitor cell fate from neurogenic to gliogenic can be central to the regulation of neurogenesis and brain circuit formation as it affects not only the number of neurons being produced but also the subsequent events of neural maturation and synaptogenesis. Drugs of abuse have been shown to cause profound defects in brain development and malformation of cerebral cortical cytoarchitecture known to associate with fetal growth suppression and CNS functional deficits later in life. Emerging evidence suggests that cocaine-induced abnormal glial development may contribute to the brain damage associated with drugs of abuse in fetus. Recently, our preliminary studies to define the roles for fibroblast growth factor 15 (FGF15) in neural stem cell growth and differentiation revealed a critical activity for FGF15 in inhibiting astrogliogenesis that in turn controls the timing of the transition from neurogenesis to gliogenesis during cortical development. Fetal exposure to cocaine caused a change in levels of FGF15 expression in the developing forebrain and glial differentiation defect. The overall goal of the present research plan is to test the hypothesis that FGF15 is a key signal regulating the transition from neurogenesis to gliogenesis in the developing cortex and that drugs of abuse may alter FGF15 signaling to cause abnormal astroglial differentiation and subsequent malformation of brain circuits in the forebrain. Aim 1 of this research plan will determine if FGF15 signaling is required and sufficient for inhibiting astrogliogenesis and maintaining neurogenic potential in cortical progenitor cell cultures as well as in FGF15 deficient mice. Aim 2 will investigate whether activation of FGF15 signaling attenuates the intracellular events triggering astrogliogenesis in the developing cortex. The results of this study will not only provide critical insight into the mechanisms controlling neuro- and glio- genesis during brain development but also facilitate a better understanding of the mechanisms of drug abuse and lead to new designs of more effective therapeutics. PUBLIC HEALTH RELEVANCE: A fundamental feature of neural development is that different cell types are generated in a precise sequence-first neurons, followed by astrocytes and then oligodendrocytes. The emerging evidence suggests that abnormalities in astroglial differentiation may be an underlying cause of drugs of abuse-induced brain damage or of other neurodegenerative or developmental disorders. Recent preliminary studies from my laboratory have pointed out a prominent activity of fibroblast growth factor 15 (FGF15) in the regulation of the transition from neurogenesis to gliogenesis during mouse cortical development. In addition, we discovered that fetal exposure to cocaine altered the level of FGF15 expression in the cortex. In the present research plan, we propose to further elucidate the roles of FGF15 in the regulation of cortical progenitor cell fate determination and glial differentiation and to determine whether alterations of FGF15 signaling could be an underlying mechanism associated with cocaine-induced malformation of brain circuits. The results of the proposed studies may provide critical insights into the adaptive processes associated with drug addiction and identify important molecular and cellular targets for pharmacological or gene therapeutic interventions to combat the pathological sequel to drugs of abuse.

描述（由申请人提供）：在脊椎动物中枢神经系统发育过程中，神经元和神经胶质细胞依次由共同祖细胞产生。控制祖细胞命运从神经源性向胶质源性转变的机制对于神经发生和脑回路形成的调节至关重要，因为它不仅影响产生的神经元数量，还影响神经成熟和突触发生的后续事件。滥用药物已被证明会导致大脑发育严重缺陷和大脑皮质细胞结构畸形，已知与胎儿生长抑制和日后中枢神经系统功能缺陷有关。新的证据表明，可卡因引起的神经胶质发育异常可能会导致胎儿因滥用药物而造成脑损伤。最近，我们的初步研究确定了成纤维细胞生长因子 15 (FGF15) 在神经干细胞生长和分化中的作用，揭示了 FGF15 在抑制星形胶质细胞生成方面的关键活性，从而控制了皮质发育过程中从神经发生到胶质细胞生成转变的时间。胎儿接触可卡因会导致发育中的前脑和神经胶质细胞分化缺陷中 FGF15 表达水平发生变化。本研究计划的总体目标是检验以下假设：FGF15 是调节发育中皮层从神经发生到胶质细胞发生转变的关键信号，滥用药物可能会改变 FGF15 信号传导，导致星形胶质细胞异常分化和随后的脑回路畸形在前脑中。该研究计划的目标 1 将确定 FGF15 信号传导是否是必要的且足以抑制星形胶质细胞生成并维持皮质祖细胞培养物以及 FGF15 缺陷小鼠中的神经发生潜力。目标 2 将研究 FGF15 信号传导的激活是否会减弱触发发育中皮质中星形胶质细胞生成的细胞内事件。这项研究的结果不仅将为大脑发育过程中控制神经和胶质生成的机制提供重要的见解，而且有助于更好地理解药物滥用的机制，并导致更有效的治疗方法的新设计。公共健康相关性：神经发育的一个基本特征是不同的细胞类型在精确的序列中产生——首先是神经元，然后是星形胶质细胞，然后是少突胶质细胞。新出现的证据表明，星形胶质细胞分化异常可能是药物滥用引起的脑损伤或其他神经退行性或发育障碍的根本原因。我实验室最近的初步研究指出，成纤维细胞生长因子 15 (FGF15) 在调节小鼠皮质发育过程中从神经发生到胶质细胞发生的转变中具有显着活性。此外，我们发现胎儿接触可卡因会改变皮质中 FGF15 的表达水平。在目前的研究计划中，我们建议进一步阐明 FGF15 在调节皮质祖细胞命运决定和神经胶质分化中的作用，并确定 FGF15 信号传导的改变是否可能是与可卡因诱导的脑回路畸形相关的潜在机制。拟议研究的结果可能为与药物成瘾相关的适应性过程提供重要见解，并确定药理学或基因治疗干预的重要分子和细胞靶点，以对抗滥用药物的病理后遗症。