PRODUCTION AND SCREENING OF MOUSE NEUROLOGICAL MUTATIONS

小鼠已经成为首要的实验哺乳动物，因为它具有分析已知基因的能力，并具有可供研究的各种新的可遗传表型变异。小鼠遗传学对哺乳动物生物学的几个复杂领域做出了重大贡献，但中枢神经系统（CNS）是一个挑战，因为它的组成部分在整个生命过程中在复杂的网络中相互连接，但仍保持很大程度的可塑性。最近在基因克隆、表达和基因靶向方面的进展有望进一步加深我们的认识，但由于CNS的相互关联且常常是冗余的功能，仅基于基因型的方法是不够的。下一步是系统地收集大量特定神经系统疾病和机制的小鼠突变体。大规模的诱变为实现这一目标提供了一个渐进的资源。我们将在杰克逊实验室建立一个神经科学诱变设施，以产生人类神经系统疾病的新小鼠模型。我们将在正常C57 BL/6 J小鼠和致敏突变体中使用ENU在全基因组和特定基因组区域筛选中产生新的突变。我们还将实施新的诱变技术，该技术依赖于用ENU以外的诱变剂处理胚胎干细胞，以使筛选更有效。我们广泛的表型范围包括运动功能，癫痫，神经性肥胖，听力，视力和学习等主要重点领域的高通量筛选，我们将与合作者合作或使访问调查员能够在摄食行为，情感障碍，感觉运动门控，药物滥用和焦虑等领域开发高通量筛选。我们将实施一项分配和共享计划，为科学界提供广泛获得无病原体小鼠、精子和胚胎的机会，以及一个实验结果数据库，以及通过互联网访问所有生成的信息和使用的协议。我们的目标是每年将新的神经模型交给科学界，并为那些希望追求它们的人保留数百个额外的潜在模型。我们的目标是最大限度地增加神经突变体的数量，使其成为重要的研究工具。

The mouse has emerged as the premiere experimental mammal because of its power for analyzing known genes and for the variety of new heritable phenotypic variants available for study. Mouse genetics has made significant contributions to several complex areas of mammalian biology, but the central nervous system (CNS) is a challenge as its components are physically inter connected throughout life in complex networks and yet retain a great degree of plasticity. Recent progress in gene cloning, expression and gene targeting promise to further our knowledge, but genotype-based approaches alone are insufficient due to the CNS' interrelated and often redundant functions. The next step is to systematically collect a large number of mouse mutants for specific neurological disorders and mechanisms. Large-scale mutagenesis offers a progressive resource towards this end. We will establish a Neuroscience Mutagenesis Facility at The Jackson Laboratory to produce new mouse models for human neurological disease. We will generate new mutations using ENU in both genome-wide and specific genomic region screens, in both normal C57BL/6J mice and sensitized mutants. We will also implement new mutagenesis technologies that rely on treating embryonic stem cells with mutagens other than ENU, to make screens more efficient. Our broad phenotypic scope includes high-throughput screens in major focus areas of motor function, epilepsy, neural obesity, hearing, vision and learning, and we will work with collaborators or enable Visiting Investigators to develop high-throughput screens in areas such as ingestive behaviors, affective disorders, sensorimotor gating, substance abuse and anxiety. We will implement a distribution and sharing plan that provides the scientific community with widespread access to pathogen- free mice, sperm and embryos, and a database for experimental results as well as Internet access to all information generated and protocols used. We aim to place new neurological models per year into hands of the scientific community, and to preserve several hundred additional potential models for those who wish to pursue them. Our goal is to maximize the number of neurological mutants that become important research tools.