COCAINE-ALTERED BRAIN GROWTH--DOPAMINE KNOCKOUT ANALYSIS

描述：(申请人摘要) 这项提议是对NIDA K02独立科学家奖的请求 允许科索夫斯基博士进一步发展他在 药物滥用研究。科索夫斯基博士是K20奖获得者，他创造了 孕期可卡因暴露对小鼠的影响的动物模型 大脑发育。吸食可卡因的母亲所生婴儿 怀孕表明头围显著减少。 表明在子宫内大脑的生长和发育受到损害。这个 科索夫斯基博士在K20的支持下开发的动物模型已经 确定了脑生长、神经解剖、行为和神经化学 经胎盘接触可卡因的后果，并具有一些特征 大脑被修饰的分子机制。这项K02研究 建议书概述了一项战略，以加深我们对 可卡因诱导的决定因素、相关因素和机制 大脑发育受阻。该研究计划概述了一项战略 利用多巴胺能信号特定缺陷的基因敲除小鼠 转导来表征分子机制，这可能是一些 孕期可卡因暴露在改变大脑发育中的作用。 通过利用具有特定元素的基因敲除小鼠 多巴胺能信号转导通路不起作用(即， 多巴胺转运蛋白和D1a受体基因敲除)，鉴定 多巴胺介导的信号负责的机制 可卡因引起的大脑结构变化将被阐明。 建议的神经解剖学方法包括MRI显微镜，一种新发展的 能够生成可分割的体数据集的技术 用于形态测量分析，提供前所未有的可视化能力 并量化三维大脑结构及其变化 由孕期接触可卡因所致。这种方法的一个强大功能是 一种独特的生物制剂(即基因敲除小鼠)与 一种创新技术(例如核磁共振显微镜)，用于服务于 一个根本性的临床问题。此外，这笔赠款将 为科索夫斯基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 可卡因的胎盘效应，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.