MOUSE MODELS FOR STUDIES OF AGING AND NEURONAL DISEASES

正常衰老和许多神经退行性疾病的特征是 神经元细胞骨架的紊乱和神经节细胞的沉积 这些蛋白质形成丝状缠结。对这一表现形式的研究 一直很慢，因为人类的神经丝是独特的，不同于 这些是实验动物的。然而，神经丝的许多方面 组装和功能是在神经元中研究得最好的--这在很大程度上是一种后 有丝分裂细胞。因此，具有讽刺意味的是，实验室动物是实验动物 选择的系统。 在这里，我们建议建立转基因小鼠系，在其中小鼠的 神经丝基因被灭活，并被一组人类 神经丝基因。在此过程的第一阶段，我们将创建一个 一种稳定的小鼠品系，其中编码三种小鼠的基因 亚基已经被定向的基因破坏而失活。这 将对突变系进行神经病理、生殖检查 特征，或未能蓬勃发展，可能会影响其使用 作为人类神经丝转基因的宿主，将在 此应用程序的第二阶段。 在此应用程序的第二阶段，我们将生产具有以下特性的小鼠系列 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。如果项目是 成功后，Taconic Farm将把这些动物分配到其 淘汰型啮齿类动物的独家许可证。 建议的商业应用 根据这一奖励将创建的鼠标线将是强大的， 研究衰老和神经退行性变的新研究工具 疾病，疑似环境毒素的毒理学研究；以及 开发新的中枢神经系统药物。

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.