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: 7432316
• 负责人: PETER P DAVIES
• 金额: $ 33.88万
• 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/7432316
• 关键词: A Mouse; ABL1 gene; Alzheimer' s Disease; Brain; Cell Cycle; Cell Death; Cessation of life; Conceptions; Cultured Cells; Dementia; Development; Family; Future; Generations; Genes; Human; Knock-out; Link; Mediating; Modeling; Mus; Nerve Degeneration; Neurons; Other Finding; Pathogenesis; Pathology; Phosphotransferases; Protein Tyrosine Kinase; Research; Rewards; Risk; Role; System; Testing; Tetanus Helper Peptide; Transgenic Mice; Work; amyloid pathology; brain cell; c-abl Proto-Oncogenes; design; hTau Mice; 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.

在此要求将优异申请延长五年时，我们专注于专业 进度和未来研究计划的发展。最近四年令人兴奋 我们对阿尔茨海默氏病发病机理的概念的发展，以及 可检验的新型假设。该假设将tau病理学的发展（激活）联系起来 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。在此优点的支持下，我们计划对此进行直接测试 假设。如果提议的工作支持该假设，则将有直接而简单的新途径 阿尔茨海默氏病的治疗剂。尽管该项目可以视为“高风险”研究，但 如果成功，奖励将是可观的。在应用程序中，导致发展的进展 审查了新的假设，研究计划旨在严格评估其通过 新的转基因小鼠的表征。在人脑和细胞培养中的平行研究，支持 其他发现将提供其他相关信息。此应用程序的具体目的是：1。 在细胞周期激活和神经元之前，确定C-ABL或ARG激活是否发生在HTAU小鼠中 死亡。 2。用诱导的，神经元特异性表达构建和分析转基因小鼠 组成性活动C-ABL。具有组成型活性ARG的诱导性，神经元特异性表达的类似小鼠 也将制作。预测是组成型活性ABL激酶的表达将导致细胞 循环激活，tau（也许是淀粉样蛋白）病理学和细胞死亡。 3。假设神经元特异性 组成性活性c-ABL（和/或ARG）的表达确实会导致神经元病理，具有诱导性的小鼠， 还将进行激酶缺陷C-ABL或ARG的神经元特异性表达。 4。检查tau的作用 在细胞周期介导的细胞死亡中。在特定目标2下制造的C-ABL和ARG小鼠将越过 tau敲除，并用人tau基因进入小鼠，以检查tau对表达的影响 病理。