PRODUCTION AND SCREENING OF MOUSE NEUROLOGICAL MUTATIONS

小鼠已经成为首屈一指的实验哺乳动物，因为它可以分析已知的基因，以及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以复杂的网络物理上相互联系，但仍保持着很大程度的可塑性。在基因克隆、表达和基因打靶方面的最新进展有望促进我们的知识，但由于中枢神经系统相互关联且往往是多余的功能，仅基于基因型的方法是不够的。下一步是系统地收集大量针对特定神经疾病和机制的小鼠突变体。大规模诱变为实现这一目标提供了一种进步的资源。我们将在杰克逊实验室建立一个神经科学突变设施，以生产新的人类神经疾病小鼠模型。我们将使用ENU在全基因组和特定基因组区域筛选中产生新的突变，在正常C57BL/6J小鼠和致敏突变体中都是如此。我们还将实施新的突变技术，这些技术依赖于用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主要重点领域的高通量筛查，如运动功能、癫痫、神经肥胖、听力、视觉和学习，我们将与合作伙伴合作，或使来访的研究人员能够在摄食行为、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查。我们将实施一项分发和共享计划，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，以及互联网访问产生的所有信息和使用的方案。我们的目标是每年将新的神经学模型交到科学界手中，并为那些希望追求这些模型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成为重要研究工具的神经学突变的数量。

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.