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

描述(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从共同的祖细胞分化而来。控制前体细胞从神经源性向胶质源性转化的机制可能是神经发生和脑回路形成调控的核心，因为它不仅影响正在产生的神经元的数量，而且还影响随后的神经成熟和突触形成事件。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，已知与胎儿生长抑制和晚年中枢神经系统功能缺陷有关。新的证据表明，可卡因诱导的神经胶质发育异常可能是与滥用药物有关的胎儿大脑损伤的原因之一。最近，我们对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进行了初步研究，发现FGF15在抑制星形胶质细胞生成方面具有关键活性，而星形胶质细胞生长因子15又控制着大脑皮质发育过程中从神经发生到胶质形成的转变时间。胎儿暴露于可卡因可导致发育中的前脑FGF15表达水平的改变和神经胶质细胞分化缺陷。目前研究计划的总体目标是检验这一假说，即FGF15是调节发育中皮质从神经发生到胶质形成的关键信号，滥用药物可能会改变FGF15信号，导致星形胶质细胞分化异常，并随后导致前脑脑回路的畸形。这项研究计划的目标1将确定在皮质前体细胞培养中以及在FGF15缺乏的小鼠中，是否需要FGF15信号来抑制星形胶质细胞的生成和维持神经生成潜力。目的2将研究激活FGF15信号是否减弱触发发育中皮质星形胶质形成的细胞内事件。这项研究的结果不仅将为脑发育过程中控制神经和神经胶质发生的机制提供关键的见解，还将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。 与公共健康相关：神经发育的一个基本特征是不同类型的细胞按精确的顺序产生--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导致的脑损伤或其他神经退行性或发育障碍的潜在原因。本实验室最近的初步研究表明，成纤维细胞生长因子15(FGF15)在小鼠皮质发育过程中具有显著的神经发生向神经胶质形成转变的调节活性。此外，我们还发现，胎儿接触可卡因改变了大脑皮质中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在调节皮质前体细胞命运和神经胶质分化中的作用，并确定FGF15信号的改变是否可能是可卡因诱导的脑回路畸形的潜在机制。拟议的研究结果可能为与药物成瘾相关的适应过程提供关键的见解，并确定重要的分子和细胞靶点，用于药物或基因治疗干预，以对抗药物滥用的病理后遗症。

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.