Building a mouse model with relevance to schizophrenia

描述(由申请人提供)：本建议书中描述的职业发展和研究计划支持被指导的申请 肯尼斯·N·菲什博士的研究科学家发展奖，意在 为应聘者提供背景知识、研究经验、 和研究管理技能，这将使他为独立的 精神分裂症的研究生涯。训练将在哈罗德L。 多里斯神经研究中心神经药理学系(Dr。 弗洛伊德·E·布鲁姆，斯克里普斯研究所所长，在 塔马斯·巴特费博士的监督。Bartfai博士非常有资格担任 候选人的导师，因为他在方法论方面的经验 他在抑郁症和精神分裂症方面的积极研究计划，以及 他致力于发展初级研究科学家。该部门 神经药理学教授强调用多学科的方法来解决 精神错乱。因此，这对候选人来说是一个理想的环境 实现了他开发多学科研究方法的目标 精神分裂症的神经生物学。研究计划的总体目标是 对卷线鼠和搅拌鼠进行彻底的分析，以确定测试 参数将用于研究新的鼠标模型并确定其 作为模型研究精神分裂症的适用性。测试将包括 大脑皮层、小脑和海马区的形态分析 NeuroZoom三维重建、免疫细胞化学分析 DA、GLU和GABA表达、定量行为测量[预脉冲 惊吓反应的抑制(PPI)]，以及它们对 临床有效的抗精神病药物(氟哌啶醇、利培酮和氯氮平)。 此外，为了进一步表征卷筒机的表型，我们将生成一个 在转基因小鼠中，reelin的表达受到时间上的调节和 生成一个鼠标模型，该模型具有条件卷动函数块以 引起大脑形态的特定变化，这是改变预脉搏所必需的 抑制和/或诱导共济失调。这些研究将增进我们的理解 神经发育异常与行为变化和意志的关系 协助开发与以下方面相关的新抗精神病药物 精神分裂症。

DESCRIPTION (provided by applicant): The career development and research program described in this proposal supports the application for a Mentored Research Scientist Development Award for Dr. Kenneth N. Fish, and is intended to provide the candidate with the background knowledge, research experience, and research management skills that will prepare him for an independent research career in schizophrenia. Training will take place at the Harold L. Dorris Neurological Research Center in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of the Scripps Research Institute, under the direct supervision of Dr. Tamas Bartfai. Dr. Bartfai is highly qualified to serve as Preceptor for the Candidate, because of his experience with the methodologies to be used, his active research program in depression and schizophrenia, and his commitment to the development of junior research scientists. The Department of Neuropharmacology emphasizes a multi-disciplinary approach to problems of mental disorders. Thus, this is an ideal environment for the Candidate to materialize his goal of developing a multidisciplinary research approach to the neurobiology of schizophrenia. The overall objective of the research plan is to perform a thorough analysis of the reeler and scrambler mice to define test parameters that will be used to study new mouse models and to determine their applicability as models to study schizophrenia. Tests will include a morphological analysis of the neocortex, cerebellum, and hippocampus using three-dimensional reconstruction with NeuroZoom, immunocytochemical analysis of DA, GLU, and GABA expression, quantitative behavioral measurements [prepulse inhibition (PPI) of the startle response], and their responsiveness to clinically effective antipsychotics (haloperidol, risperidone, and clozapine). In addition, to further characterize the reeler phenotype we will generate a transgenic mouse in which reelin expression is temporally regulated and generate a mouse model that has a conditional block of reelin function to induce specific changes in brain morphology that are required to alter prepulse inhibition and/or induce ataxia. These studies will advance our understanding of how neurodevelopmental abnormalities relate to behavioral changes and will assist in the development of new antipsychotic drugs with relevance to schizophrenia.