COCAINE-ALTERED BRAIN GROWTH--DOPAMINE KNOCKOUT ANALYSIS

描述：（申请人摘要） 该提案是NIDA K02独立科学家奖的申请， 允许Kosofsky博士进一步发展他在该领域的研究计划， 药物滥用研究 Kosofsky博士是K20奖获得者，他创造了 妊娠期可卡因暴露对小鼠的影响的动物模型 大脑发育 在怀孕期间滥用可卡因的母亲所生的婴儿 怀孕表明头围显著减小 表明子宫内大脑生长和发育受损。 的 Kosofsky博士在K20的支持下开发的动物模型， 确定了大脑的生长，神经解剖学，行为学和神经化学 经胎盘可卡因暴露的后果，并已表征了一些 改变大脑的分子机制 K02研究 提案概述了一项战略，以进一步了解 可卡因引起的神经系统疾病的决定因素、相关因素和机制 破坏大脑发育。 该研究计划概述了一项战略， 利用在多巴胺能信号中具有特定缺陷的基因敲除小鼠， 转导，以表征分子机制，这可能是一些 妊娠期接触可卡因对大脑发育的影响 通过利用基因敲除小鼠， 多巴胺能信号转导途径使多巴胺（即， 多巴胺转运蛋白敲除和D1a受体敲除），鉴定 多巴胺能介导的信号负责 将阐明可卡因诱导的脑结构改变。 提出的神经解剖学方法包括MRI显微镜，一种新开发的 能够生成可分割的体数据集的技术 用于形态分析，提供了前所未有的可视化能力， 并量化三维大脑结构及其变化 是由于妊娠期接触可卡因所致 这种方法的一个优点是 独特的生物制剂（即，敲除小鼠）， 创新技术（例如，MRI显微镜），用于 一个至关重要的临床问题 此外，这笔赠款将 为Kosofsky博士的职业发展做出重大贡献， 他有机会进一步发展他的研究计划， 可卡因的经胎盘作用，通过创新和应用这些 途径和方法。

DESCRIPTION: (Applicant's Abstract) This proposal is a request for a NIDA K02 Independent Scientist Award to allow Dr. Kosofsky to further develop his research program in the field of drug abuse research. Dr. Kosofsky is a K20 award recipient, who has created an animal model (in mice) of the effects of gestational cocaine exposure on brain development. Infants born to mothers who abuse cocaine during gestation demonstrate a significant decrease in head circumference indicative of in utero compromise of brain growth and development. The animal model Dr. Kosofsky developed while being supported by the K20 has identified brain growth, neuroanatomic, behavioral, and neurochemical consequences of transplacental cocaine exposure, and has characterized some of the molecular mechanisms whereby brain is modified. This K02 research proposal outlines a strategy to further our understanding regarding the determinants, correlates and mechanisms underlying the cocaine-induced disruption of brain development. The research program outlines a strategy to utilize knockout mice that have specific deficits in dopaminergic signal transduction to characterize molecular mechanisms which may underlie some of the effects of gestational cocaine exposure in altering brain development. By utilizing knockout mice which have specific elements within the dopaminergic signal transduction pathway rendered inoperative (i.e., dopamine transporter knockouts and D1a receptor knockouts), identification of mechanisms by which dopaminergic-mediated signals are responsible for cocaine-induced alterations in brain structure will be elucidated. Neuroanatomic methods proposed include MRI microscopy, a newly developed technology capable of generating volumetric data sets that can be segmented for morphometric analysis, providing an unprecedented ability to visualize and quantitate 3-dimensional brain structure, and alterations thereof resulting from gestational cocaine exposure. One power of this approach is the combination of a unique biologic preparation (i.e., knockout mice) with an innovative technology (e.g., MRI microscopy), utilized in the service of a clinical problem of fundamental importance. In addition, this grant will contribute significantly to Dr. Kosofsky's career development by offering him the opportunity to further develop his research program on the transplacental effects of cocaine, by innovating and applying these approaches and methods.