A Mouse Model of Tau Pathology in AD & Other Dementias

AD 中 Tau 蛋白病理学的小鼠模型

• 批准号: 7586175
• 负责人: PETER P DAVIES
• 金额: $ 34.03万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586175
• 关键词: A Mouse; ABL1 gene; Alzheimer' s Disease; Brain; Cell Culture Techniques; Cell Cycle; Cell Death; Cessation of life; Conceptions; Dementia; Development; Family; Future; Generations; Genes; Human; Knock-out; Link; Mediating; Modeling; Mus; Nerve Degeneration; Neurons; Pathogenesis; Pathology; Phosphotransferases; Protein Tyrosine Kinase; Research; Rewards; Role; System; Testing; Tetanus Helper Peptide; Transgenic Mice; Work; amyloid pathology; brain cell; c-abl Proto-Oncogenes; design; hTau Mice; high risk; inhibitor/antagonist; mouse model; novel; novel therapeutics; tau Proteins

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.

在将MERIT申请延长五年的请求中，我们重点关注了以下主要问题： 发展的进展和未来的研究计划。在过去的四年里， 我们对阿尔茨海默病发病机制的概念的发展，以及 新颖的，可验证的假设这一假说将tau蛋白病理学的发展、tau蛋白的激活 细胞周期的组成部分和神经元变性，这可能是由于abl家族的激活 蛋白质酪氨酸激酶。在MERIT扩展的支持下，我们计划直接测试 假说.如果假设是支持的工作提出，将有直接和简单的途径，以新的 阿尔茨海默病的治疗方法。虽然这个项目可以被认为是"高风险"的研究， 如果成功的话，回报会很可观。在应用上，以进步带动发展， 新的假设进行审查，研究计划的目的是严格评估它的有效性，通过 新的转基因小鼠的特征。人脑和细胞培养的平行研究，由 其他发现，将提供更多的相关信息。本申请的具体目的是：1.到 确定c-abl或Arg活化是否在细胞周期活化之前发生在hTau小鼠中，以及神经元活化是否发生在hTau小鼠中。 死亡2.构建和分析具有可诱导的神经元特异性表达的转基因小鼠， 组成型活性c-abl。具有可诱导的、神经元特异性表达组成型活性Arg的类似小鼠 也将作出。预测是组成型活性ABL激酶的表达将导致细胞凋亡。 周期激活、tau（可能还有淀粉样蛋白）病理学和细胞死亡。3.假设神经元特异性 组成型活性c-abl（和/或Arg）的表达确实引起神经元病理学，具有可诱导的， 还将进行激酶缺陷型c-abl或Arg的神经元特异性表达。4.研究tau蛋白的作用 细胞周期介导的细胞死亡。根据特定目标2制备的c-abl和Arg小鼠将被杂交到 tau基因敲除，并进入小鼠与人类tau基因，以检查tau蛋白的表达的影响， 病理