SNAP-25 EXPRESSION AND HYPERACTIVITY IN COLOBOMA MICE

COLOBOMA 小鼠中的 SNAP-25 表达和过度活跃

• 批准号: 3388497
• 负责人: MICHAEL COLIN WILSON
• 金额: $ 27.08万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3388497
• 关键词: Mus musculus; amphetamines; artificial chromosomes; attention deficit disorder; behavior test; behavioral genetics; developmental neurobiology; disease /disorder model; gene complementation; gene deletion mutation; gene expression; genetic enhancer element; genetic library; genetic promoter element; genetic strain; genetically modified animals; laboratory rabbit; methylphenidate; model design /development; nerve /myelin protein; nucleic acid probes; nucleic acid sequence; phenotype; protein structure function; restriction fragment length polymorphism; synapses

The establishment and modulation of specific patterns of neural synaptic connectivity is crucial to normal brain function. It is likely, moreover, that abnormalities in synapse formation may, contribute to neurologic and psychiatric disorders. The overall objective of this research program is to achieve an understanding of the molecular mechanisms which underlie the regulation of genes that contribute to this process. The direct aims of the proposed investigation are to evaluate the involvement of SNAP-25, a highly evolutionary conserved presynaptic nerve terminal protein, in the spontaneous hyperactivity disorder exhibited by the mouse neurological mutant Coloboma, Cm. It is proposed that the Cm mutation in mice that encompasses a deletion of the Snap-25 gene provides a model for Attention Deficit Hyperactivity Disorder (ADHD) of children. To achieve these goals, the genomic structure and scope of the Cm mutation will be defined by analysis of restriction fragment length polymorphisms (RFLPS) of interspecies hybrids between Coloboma and Mus spretus. Probes to genes known to neighbor the Snap-25 locus and probes derived from yeast artificial chromosome (YAC) libraries will be used to identify which specific sequences are deleted and thereby map the boundaries of the Cm deletion. The second specific aim is to characterize fully the hyperactive locomotor behavior of Cm/+ mutant mice in response to psychostimulant drugs. These studies will reveal whether dopaminergic systems are involved and respond in a manner similar to that observed in ADHD. The third aim is to attempt to rescue the behavioral deficits of Coloboma mice through complementation by deriving transgenic animals overexpressing the gene and crossbreeding with the mutant strain. The final aim is to evaluate the function of Snap-25 gene expression directly in hyperactivity and behavior by specifically abolishing its expression through targeted gene disruption and reintegration into the germline of transgenic animals. Through these studies, we anticipate that a new and useful model of ADHD will be established and the possible contribution of SNAP-25 or additional factors involved in the development of hyperactivity disorders will be identified.

神经突触特定模式的建立和调节 连接性对于正常的大脑功能至关重要。 此外，很可能， 突触形成的异常可能有助于神经系统和 精神疾病。 该研究计划的总体目标是 以了解其背后的分子机制 有助于这一过程的基因的调节。 直接目的是 拟议的调查是为了评估 SNAP-25 的参与， 高度进化保守的突触前神经末梢蛋白 小鼠神经系统表现出的自发性多动症 突变型缺损，Cm。 据推测，小鼠体内的 Cm 突变 包含 Snap-25 基因的删除，提供了注意力模型 儿童缺陷多动障碍（ADHD）。 为了实现这些目标，Cm突变的基因组结构和范围 将通过限制性片段长度多态性分析来定义 （RFLPS）的 Coloboma 和 Mus spretus 之间的种间杂交。 探头 已知与 Snap-25 基因座相邻的基因和源自酵母的探针 人工染色体（YAC）文库将用于识别哪些 特定序列被删除，从而绘制出 Cm 的边界 删除。 第二个具体目标是充分描述多动症的特征 Cm/+突变小鼠响应精神兴奋剂的运动行为 药物。 这些研究将揭示多巴胺能系统是否参与其中 并以类似于多动症中观察到的方式做出反应。 第三个目标是 试图通过以下方式挽救 Coloboma 小鼠的行为缺陷 通过衍生过度表达该基因的转基因动物来实现互补 与突变株杂交。 最终目的是评估 Snap-25 基因表达直接在多动和行为中发挥作用 通过靶向基因破坏专门消除其表达 并重新融入转基因动物的种系。 通过这些研究，我们预计会出现一种新的、有用的 ADHD 模型 将建立并可能贡献 SNAP-25 或其他 参与多动症发展的因素将是 确定。