A Mouse Model of Tau Pathology in AD & Other Dementias

在这项将功绩申请再延长五年的请求中，我们将重点放在主要的 研究进展和未来研究计划的发展。在过去的四年里，我们看到了非常激动人心的 我们对阿尔茨海默病发病机制的概念的发展，以及 新颖的、可检验的假设。这一假说将tau病理的发展、激活 细胞周期和神经元变性的组成部分，这可能是由于ABL家族的激活 蛋白酪氨酸激酶。在这一优点扩展的支持下，我们计划直接测试这一点 假设。如果这一假设得到了所提出的工作的支持，将会有直接和简单的途径来获得新的 阿尔茨海默病的治疗学。虽然这个项目可以被认为是“高风险”的研究，但 如果它成功了，回报将是可观的。在应用中，导致发展的进展 回顾了新的假设，并设计了研究计划，以通过以下方式严格评估其有效性 新转基因小鼠的特性。人脑和细胞培养的平行研究，由 其他发现，将提供更多相关信息。本申请的具体目的是：1. 确定hTau小鼠在细胞周期激活和神经元激活之前是否存在c-abl或Arg激活 死亡。2.构建和分析可诱导的神经元特异性表达的转基因小鼠 构成活性c-abl。具有可诱导的、神经元特异性表达结构性活性Arg的相似小鼠 也将被制作成。预测是，结构性活性ABL激酶的表达将导致细胞 循环激活、tau(也许还有淀粉样蛋白)病理和细胞死亡。3.假设神经元特异性 C-ABL(和/或Arg)的表达确实会导致神经元病理，可诱导的小鼠， 还将进行神经元特异性表达激酶缺陷的c-abl或Arg。4.研究tau的作用 在细胞周期中介导细胞死亡。在特定目标2下制备的c-abl和Arg小鼠将被杂交到 Tau基因敲除，并进入携带人tau基因的小鼠体内，以检测tau对人tau基因表达的影响。 病理学。

In this request to extend the MERIT application for an additional five years, we have focused on the major developments in both progress and plans for the future research. The last four years has seen very exciting developments in our conception of the pathogenesis of Alzheimer's disease, and the development of a novel, testable hypothesis. This hypothesis links the development of tau pathology, the activationof components of the cell cycle and neuronal degeneration, which may be due to the activation of the abl family of protein tyrosine kinases. With the support of this MERIT extension we plan direct testing of this hypothesis. If the hypothesis is supported by the work proposed, there will be direct and simple paths to new therapeutics for Alzheimer's disease. Although this project could be considered "high risk" research, the rewards will be considerable if it is successful. In the application, the progress leading to the development of the new hypothesis is reviewed, and the research plan is designed to rigorously assess it's validity through the characterization of new transgenic mice. Parallel studies in human brain and cell culture, supported by other finds, will provide additional relevant information. The specific aims of this application are: 1. To establish whether c-abl or Arg activation occurs in the hTau mouse prior to cell cycle activation and neuronal death. 2. To construct and analyze transgenic mice with inducible, neuron-specific expressionof constitutively active c-abl. Similar mice with inducible, neuron-specific expression of constitutively active Arg will also be made. The prediction is that expression of the constitutively active abl kinases will result in cell cycle activation, tau (and perhaps amyloid) pathology, and cell death. 3. Assuming that neuron-specific expression of constitutively active c-abl (and/or Arg) does cause neuronal pathology, mice with inducible, neuron-specific expression of kinase-defective c-abl or Arg will also be made. 4. To examine the role of tau in cell cycle mediated cell death. The c-abl and Arg mice made under specific aim 2 will be crossed into the tau knockout, and into mice with the human tau gene, to examine the influence of tau on the expressionof pathology.