MOUSE MODELS FOR STUDIES OF AGING AND NEURONAL DISEASES

正常衰老和许多神经退行性疾病的标志是 神经元细胞骨架的紊乱和神经元细胞内 这些蛋白质是丝状缠结。研究这种表现 因为人类的神经丝是独一无二的， 实验室动物。 然而，神经丝的许多方面 组装和功能最好在神经元中进行研究-- 有丝分裂细胞 因此，具有讽刺意味的是，实验动物是实验动物。 选择系统。 在此，我们提出创建转基因小鼠品系，其中小鼠的 神经丝基因被灭活，并被一组人类 神经丝基因 在这个过程的第一阶段，我们将创建一个 稳定的小鼠品系，其中编码三种小鼠 亚基已经被靶向基因破坏失活。 这 将对突变系进行神经病理学、生殖检查 特性，或未能茁壮成长，可能会危及其使用 作为人类神经丝转基因的宿主， 第二阶段的应用。 在本申请的第二阶段，我们将生产小鼠品系， 在神经丝基因和网络方面被“人性化” 使用标准的转基因小鼠范例。如果项目 如果成功，Taconic农场将根据其 独家授权的击倒啮齿动物。 建议的商业应用 在这项资助下创建的鼠标线将是强大的， 研究衰老和神经退行性疾病的新工具 疾病，用于可疑环境毒素的毒理学研究，以及 新型中枢神经系统药物的开发。

The hallmark of normal aging and of many neurodegenerative diseases is the derangement of the cytoskeleton of the neuron and the deposition of these proteins as filamentous tangles. Research into this manifestation has been slow because human neurofilaments are unique and different from those of laboratory animals. However, many aspects of neurofilament assembly and function are best studied in the neuron -- a largely post- mitotic cell. Thus, ironically, laboratory animals are the experimental systems of choice. Herein we propose to create transgenic mouse lines in which the mouse's neurofilament genes are inactivated and replaced with a set of human neurofilament genes. In Phase I of this process, we will create a stable line of mice in which the genes encoding the three murine subunits have been inactivated by a targeted gene disruption. This mutant line will be examined for neuropathology, reproductive characteristics, or a failure to thrive that might compromise its use as a host for human neurofilament transgenes that will be introduced in Phase II of this application. In Phase II of this application we will produce lines of mice that have been "humanized" with respect to their neurofilament genes and networks using the standard transgenic mouse paradigm. If the project is successful, Taconic Farms will distribute these animals under its exclusive license for knockout rodents. PROPOSED COMMERCIAL APPLICATION The mouse lines that will be created under this grant will be powerful, new research tools for the study of aging and neuro-degenerative diseases, for toxicologic studies of suspected environmental toxins, and the development of new CNS drugs.