Mutant tubulins confer resistance to pathological tau

突变微管蛋白赋予对病理性 tau 蛋白的抵抗力

• 批准号: 10283016
• 负责人: Sarah Jean Zimmerman Benbow
• 金额: $ 12.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283016
• 关键词: Address; Affect; Alzheimer' s Disease; Axonal Transport; Behavioral; Binding; Biochemical; Biology of Aging; Caenorhabditis elegans; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Cytoskeleton; Defect; Development; Disease; Disease Progression; Frontotemporal Lobar Degenerations; Genes; Goals; Healthcare Systems; Human; In Vitro; Journals; Knowledge; Laboratories; Leadership; MAPT gene; Measures; Mediating; Medical; Methods; Microtubule Polymerization; Microtubules; Modeling; Molecular; Motor; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathologic; Pathology; Phase; Phenotype; Phosphorylation; Play; Point Mutation; Prevalence; Principal Investigator; Process; Property; Proteins; Research; Research Personnel; Resistance; Resources; Role; System; Tauopathies; Testing; Toxic effect; Training; Transgenic Organisms; Translating; Translations; Tubulin; United States Department of Veterans Affairs; Universities; Washington; Work; age related; aging population; base; biophysical techniques; career; career networking; cell motility; chronic traumatic encephalopathy; experimental study; gain of function; genetic approach; health care economics; improved; interest; live cell imaging; meetings; mutant; new therapeutic target; novel therapeutic intervention; protein aggregation; reconstitution; skills; social; sound; tau Proteins; tau aggregation; tau-microtubule interaction

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.

项目总结/摘要 病理性tau蛋白存在于许多与年龄相关的疾病（tau蛋白病）中，包括 阿尔茨海默病（AD）。随着老年人口的增加，这些疾病的流行将 成为巨大的医疗、经济和社会负担。迄今为止，临床上没有 经过验证的疾病改变疗法。最近，我们发现突变微管蛋白修饰 转基因C. elegans模型，减少人类tau诱导的运动 缺陷和神经变性。我们假设突变的微管蛋白改善了tau诱导的 C. elegans通过改变tau-微管相互作用。为了验证我们的假设， 建议1）使用C。elegans来确定微管蛋白抑制的水平是否基于微管蛋白 表达水平2）使用重建的体外系统来测试微管蛋白突变是否影响tau蛋白。 微管相互作用和3）使用哺乳动物原代神经元来测试突变微管蛋白是否 影响微管的性质和功能。建议的项目将阐明 突变型微管蛋白抑制tau蛋白诱导的病理和tau蛋白微管的机制 交互.此外，这项工作将有助于更好地了解细胞骨架， 神经退行性疾病 我的目标是作为一名主要研究者，致力于发现 Tau蛋白病的分子机制以及细胞骨架网络在 神经变性为了实现这一目标，我的培训计划侧重于1）扩大我的技术 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 3）提高实验室领导技能，扩大我的专业知识， 网络 华盛顿大学和退伍军人事务部普吉特湾医疗保健系统 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，期刊俱乐部， 会议创造了许多机会，通过与 医学和科学界在AD相关研究中的作用。