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

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从共同祖细胞产生。控制祖细胞命运从神经源性向胶质源性转变的机制可能是调节神经发生和脑回路形成的核心，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。药物滥用已被证明会导致大脑发育的严重缺陷和大脑皮质细胞结构的畸形，这些已知与胎儿生长抑制和生命后期中枢神经系统功能缺陷有关。越来越多的证据表明，可卡因诱导的神经胶质发育异常可能导致与药物滥用有关的胎儿脑损伤。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形成方面具有关键活性，从而控制皮层发育过程中从神经发生向胶质细胞发生转变的时间。胎儿暴露于可卡因导致发育中的前脑和胶质分化缺陷中FGF15表达水平的变化。本研究计划的总体目标是验证以下假设：FGF15是发育中的皮层中调节神经发生向胶质发生转变的关键信号，滥用药物可能改变FGF15信号，导致前脑星形胶质细胞异常分化和随后的脑回路畸形。本研究计划的目的1将确定在皮质祖细胞培养和FGF15缺陷小鼠中，FGF15信号传导是否需要和充分抑制星形胶质细胞形成和维持神经发生潜力。目的2将研究FGF15信号的激活是否会减弱发育中的皮层中触发星形胶质细胞形成的细胞内事件。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细胞发生的机制提供关键的见解，而且还将促进对药物滥用机制的更好理解，并导致新的更有效的治疗方法的设计。

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.