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

描述（由申请人提供）：神经元和神经胶质细胞在脊椎动物CNS发育过程中依次从共同祖细胞产生。支配祖细胞命运从神经源性向神经胶质源性转变的机制对于神经发生和脑回路形成的调节是重要的，因为它不仅影响产生的神经元的数量，而且影响随后的神经成熟和突触发生的事件。滥用药物已被证明会导致大脑发育的严重缺陷和大脑皮层细胞结构的畸形，已知这些缺陷和畸形与胎儿生长抑制和生命后期的CNS功能缺陷有关。新的证据表明，可卡因诱导的异常胶质细胞发育可能有助于与滥用药物有关的胎儿脑损伤。最近，我们的初步研究，以确定成纤维细胞生长因子15（FGF 15）在神经干细胞的生长和分化的作用，揭示了一个关键的活动，FGF 15在抑制星形胶质细胞，反过来控制皮质发育过程中的神经发生到胶质细胞发生的转变的时间。胎儿暴露于可卡因引起的FGF 15表达水平的变化，在发展中的前脑和神经胶质细胞分化缺陷。本研究计划的总体目标是检验以下假设：FGF 15是调节发育中皮质从神经发生向胶质细胞发生转变的关键信号，滥用药物可能会改变FGF 15信号传导，导致前脑星形胶质细胞分化异常和随后的脑回路畸形。本研究计划的目的1将确定是否需要FGF 15信号传导，并足以抑制星形胶质细胞生成和维持皮质祖细胞培养物以及FGF 15缺陷小鼠的神经发生潜力。目的2将研究是否激活FGF 15信号减弱细胞内事件触发星形胶质细胞在发育中的皮质。这项研究的结果不仅将为大脑发育过程中控制神经元和胶质细胞生成的机制提供重要的见解，而且还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。 公共卫生相关性：神经发育的一个基本特征是，不同类型的细胞以精确的顺序产生-首先是神经元，其次是星形胶质细胞，然后是少突胶质细胞。新出现的证据表明，星形胶质细胞分化的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。最近的初步研究，从我的实验室已经指出了一个突出的活性成纤维细胞生长因子15（FGF 15）在调节从神经发生到胶质细胞发生在小鼠皮层发育的过渡。此外，我们发现胎儿暴露于可卡因改变了皮质中FGF 15的表达水平。在本研究计划中，我们建议进一步阐明FGF 15在调节皮质祖细胞命运决定和胶质细胞分化中的作用，并确定FGF 15信号转导的改变是否可能是可卡因诱导的脑回路畸形的潜在机制。拟议研究的结果可能会提供关键的见解与药物成瘾的适应过程，并确定重要的分子和细胞的药理学或基因治疗干预措施，打击滥用药物的病理后果的目标。

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.