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: 3388498
• 负责人: MICHAEL COLIN WILSON
• 金额: $ 26.82万
• 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/3388498
• 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.

神经突触特异性模式的建立和调节 连通性对正常的大脑功能至关重要。 此外， 突触形成的异常可能会导致神经系统疾病， 精神疾病 本研究计划的总体目标是 以了解其背后的分子机制 基因的调节，有助于这一过程。 的直接目的 拟议的调查是评估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障碍 突变体Coloboma，Cm. 有人提出，小鼠中的Cm突变， 包括Snap-25基因的缺失提供了一个模型， 儿童多动症（ADHD）。 为了实现这些目标，基因组结构和范围的Cm突变 将通过分析限制性片段长度多态性来定义 （RFLPS）之间的种间杂种Coloboma和小鼠spretus。 探针 已知邻近Snap-25基因座的基因和来自酵母的探针 人工染色体（YAC）文库将用于鉴定 特定序列被删除，从而映射Cm的边界 删除。 第二个具体目标是充分描述多动症 精神兴奋剂对Cm/+突变小鼠运动行为影响 毒品 这些研究将揭示多巴胺能系统是否参与 并以类似于ADHD中观察到的方式做出反应。 第三个目标是 试图挽救Coloboma小鼠的行为缺陷， 通过衍生过表达该基因的转基因动物进行互补， 与突变株杂交。 最终目的是评估 Snap-25基因表达在多动症和行为中的直接作用 通过靶向基因破坏特异性地消除其表达， 并重新整合到转基因动物的种系中。 通过这些研究，我们预计，一个新的和有用的模型多动症 将建立和SNAP-25或其他可能的贡献 参与多动症发展的因素将是 鉴定