Mutant tubulins confer resistance to pathological tau

项目摘要/摘要 病理性tau存在于许多与年龄相关的疾病(Tauopy)中，包括 阿尔茨海默病(AD)。随着老龄化人口的增加，这些疾病的流行将 成为巨大的医疗、经济和社会负担。到目前为止，还没有临床上 已证实的疾病改变了治疗方法。最近，我们发现突变的微管蛋白可以修饰 转基因线虫模型中的tau病样表型，降低了tau诱导的人类运动能力 缺陷和神经退化。我们假设突变的微管蛋白可以改善tau诱导的 通过改变tau-微管相互作用在线虫中的表型。为了检验我们的假设，我们 建议1)使用线虫来确定微管蛋白抑制水平是否基于微管蛋白 表达水平2)使用重组的体外系统来测试微管蛋白突变是否影响tau- 微管相互作用和3)使用哺乳动物初级神经元来测试突变的微管蛋白 影响微管的特性和功能。建议的项目将阐明 突变型微管蛋白抑制tau诱导的病理和tau微管的机制 互动。此外，这项工作将有助于更好地理解细胞骨架 神经退行性疾病。 我的目标是发展自己的职业生涯，成为一名致力于发现 肌萎缩侧索硬化症的分子机制及细胞骨架网络在其中的作用 神经退行性变。要做到这一点，我的培训计划侧重于1)扩展我的技术能力 结合生物物理方法和活细胞成像的工具包2)获得更多知识 在老化的生物学中提高实验室领导技能和扩展我的专业技能 网络。 华盛顿大学和退伍军人事务部普吉特健全的医疗保健系统 分享了大量对阿尔茨海默氏症和其他神经退行性疾病感兴趣的研究人员 条件。有大量的智力资源，如研讨会、杂志俱乐部和 创造大量机会的会议通过与 医学界和科学界对AD的相关研究。

Project Summary/Abstract Pathological tau is present in a number of age-related diseases (tauopathies) including Alzheimer's Disease (AD). With a rising aged population the prevalence of these diseases will become an enormous healthcare, economic and social burden. To-date there are no clinically proven disease altering treatments. Recently, we have discovered mutant tubulin modifies tauopathy-like phenotypes in transgenic C. elegans models, reducing human tau-induced motility deficits and neurodegeneration. We hypothesize that mutant tubulin ameliorates tau-induced phenotypes in C. elegans by altering tau-microtubule interactions. To test our hypothesis we propose to 1) use C. elegans to determine if the level of tubulin suppression is based in tubulin expression level 2) use reconstituted in vitro systems to test whether tubulin mutations affect tau- microtubule interactions and 3) use mammalian primary neurons to test whether mutant tubulin impacts microtubule properties and function. The proposed projects will elucidate the mechanisms of mutant tubulin suppression of tau induced-pathology and tau-microtubule interactions. Additionally, this work will contribute greater understanding of the cytoskeleton in neurodegenerative disease. My goal is to develop a career as a principal investigator devoted to the discovery of the molecular mechanisms underpinning tauopathies and the roles the cytoskeletal network play in neurodegeneration. To accomplish this, my training plan focuses on 1) expanding my technical toolkit to incorporate biophysical approaches and live cell imaging 2) gaining greater knowledge in the biology of aging 3) improving skills in laboratory leadership and expanding my professional network. The University of Washington and the Veterans Affairs Puget Sound Health Care System share an abundance of researchers interested in Alzheimer's and other neurodegenerative conditions. There are substantial intellectual resources such as seminars, journal clubs and meetings that create numerous opportunities broaden my perspective through interactions with the medical and scientific community in AD-related research.