RANDOM MUTAGENESIS SCREEN FOR BEHAVIORAL MUTANTS IN MICE

我们研究的长期目标是确定新的行为 小鼠的突变可能允许解剖遗传途径 潜在的神经生物学过程。有限的可得性 合适的动物模型阻碍了对复杂疾病的研究 神经精神疾病，如精神分裂症，严重的情感性 精神障碍和睡眠障碍。药理学和外科操作 已经被用来诱导模拟人类某些方面的行为 实验动物模型中的紊乱；然而，这些模型代表 表型，并不反映异常行为的遗传原因 动物。这项提案中概述的方法涉及随机突变。 在小鼠基因组中，使用一种有效的诱变剂N-乙基-N-亚硝脲(ENU)， 以及对异常行为表型的筛查；尤其是干扰 休息：活动行为和改变的声学惊吓反应。小说 突变的表型特征将基于它们的染色体 区位分析和互补分析。 这个项目是一个更大的努力的一部分--NIH调查员发起的 互动研究项目(IRPG)-执行全基因组搜索 显性行为突变并使小鼠的一部分饱和 带有隐性突变的基因组。随机诱变组合(IRPG 一项提案)，努力创建删除项(IRPG两项提案) 在小鼠5号染色体上的30 cM区域，在 在遗传和分子水平上，将允许隐性的鉴定 2%小鼠的两代饱和筛查突变 基因组。IRPG的努力将使鉴定、表型分析和 发育和行为突变的图谱以及鉴定 其显性行为异常可能是由于潜在的 发育和/或神经解剖和神经病理缺陷。

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.