RANDOM MUTAGENESIS SCREEN FOR BEHAVIORAL MUTANTS IN MICE

我们研究的长期目标是识别新的行为 小鼠中的突变可能允许解剖遗传途径 潜在的神经生物学过程的有限可用性 合适的动物模型阻碍了复杂的研究 神经精神疾病，如精神分裂症，严重的情感障碍， 和睡眠障碍。药理学和手术操作 已经被用来诱导模仿人类行为的行为， 实验动物模型中的疾病;然而，这些模型代表了 表型复制，并不反映遗传原因的异常行为， 动物该建议中概述的方法涉及随机诱变 的小鼠基因组，使用一种有效的诱变剂N-乙基-N亚硝基脲（ENU）， 并筛选异常行为表型;特别是， 休息：活动行为和改变的声音惊吓反应。小说 突变将基于它们的染色体特征进行表型表征。 定位与互补分析。 该项目是NIH研究者发起的一项更大努力的一部分 互动研究项目（IRPG）-进行全基因组搜索， 显性行为突变，并使小鼠的一部分 基因组隐性突变。随机诱变（IRPG） 一个提案），并努力创建删除（IRPG两个提案） 在小鼠5号染色体上的30 cM区域， 遗传和分子水平，将允许识别隐性 在两代饱和筛选中对2%的小鼠进行突变 基因组IRPG的努力将允许识别，表型分析和 绘制发育和行为突变体的图谱， 突变体的显性行为异常可能是由于潜在的 发育和/或神经解剖学和神经病理学缺陷。

The long term objective of our studies is to identify novel behavioral mutations in mice which may allow the dissection of genetic pathways underlying neurobiological processes. The limited availability of appropriate animal models has hindered research in complex neuropsychiatric illnesses such as schizophrenia, major affective disorders, and sleep disorders. Pharmacologic and surgical manipulations have been used to induce behaviors that simulate aspects of human disorders in laboratory animal models; however, these models represent phenocopies and do not reflect genetic causes of aberrant behavior in the animal. The approach outlined in this proposal involves random mutagenesis of the mouse genome, using a potent mutagen N-ethyl-N nitrosourea (ENU), and screens for abnormal behavioral phenotypes; in particular, disrupted rest: activity behavior and altered acoustic startle response. Novel mutations will be phenotypically characterized based on their chromosomal location and complementation analysis. This project is part of a larger effort-NIH Investigator-Initiated Interactive Research Project (IRPG)- to perform a genome-wide search for dominant behavioral mutations and to saturate a portion of the mouse genome with recessive mutations. A combination of random mutagenesis (IRPG one proposal) with an effort to create deletions (IRPG two proposal) across the 30 cM region on mouse chromosome 5, well characterized at the genetic and molecular level, will allow the identification of recessive mutations in a two generation saturation screen for 2% of the mouse genome. The IRPG effort will allow identification, phenotypic analysis and mapping of development and behavioral mutants as well as identification of mutants whose dominant behavioral anomalies may be due to underlying development, and/or neuroanatomical and neuropathological defects.