GENETIC DISRUPTION OF TAU METABOLISM IN TAUOPATHIES

描述（由申请人提供）：本研究和培训计划的总体目标是确定tau蛋白病的分子机制。Tau聚集体是Tau蛋白病的标志性病理学特征，所述Tau蛋白病包括阿尔茨海默病、进行性核上性麻痹、额颞叶痴呆、皮质基底节变性和皮克病。虽然帕金森病通常不被表征为tau蛋白病，但常见的tau基因（MAPT）单倍型是疾病的既定风险因素。该项目旨在确定tau蛋白病的分子机制，将提高我们对tau遗传学如何影响tau生物学的理解，并将为治疗干预提供新的途径。研究人员塞莱斯特·卡奇博士将获得干细胞生物学、基因组学和轴突成像方面的高级培训，以支持一种创新方法，即建立新型细胞模型，该模型使用人类诱导多能干细胞（iPSC）衍生的神经元、锌指核酸酶和轴突成像，以研究编码tau蛋白的基因MAPT的遗传变化在多大程度上破坏tau蛋白病中的tau代谢。Alison Goate博士、Marc Diamond博士、Jeffrey Milbrandt博士和Yadong Huang博士分别是人类和分子遗传学、tau蛋白聚集、轴突变性和干细胞生物学领域的国际公认专家。该提案的目标是确定与tau蛋白病风险相关的tau基因组变体如何使用人类iPSC衍生的神经元促进这些疾病的发展。该提议的总体假设是存在共同的机制，疾病突变和风险单倍型通过该机制破坏tau代谢并促成疾病发病机制。为了定义这些共同的机制，我将测量来自疾病突变和风险单倍型携带者的iPSC衍生神经元中tau代谢的几种模式。通过这项研究和指导培训计划，Karch博士将开始定义Tau蛋白病的分子机制，并将建立新的实验工具和方法，这将为作为独立的翻译神经科学家的职业生涯奠定基础。

DESCRIPTION (provided by applicant): The overall goal of this research and training plan is to define the molecular mechanisms underlying tauopathies. Tau aggregates are a hallmark pathological feature of tauopathies, which include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration and Pick's disease. While Parkinson's disease is not usually characterized as a tauopathy, a common tau gene (MAPT) haplotype is an established risk factor for disease. This project aims to define the molecular mechanisms underlying tauopathies, will improve our understanding of how tau genetics influences tau biology, and will inform novel avenues for therapeutic intervention. The investigator, Dr. Celeste Karch, will gain advanced training in stem cell biology, genomics, and axonal imaging in support of an innovative approach that establishes novel cell models that use human induced pluripotent stem cell (iPSC)-derived neurons, zinc finger nucleases, and axonal imaging to study the extent to which genetic changes in MAPT, the gene that encodes the tau protein, disrupts tau metabolism in tauopathies. The mentors, who were selected for this training, Drs. Alison Goate, Marc Diamond, Jeffrey Milbrandt, and Yadong Huang, are internationally recognized experts in the fields of human and molecular genetics, tau aggregation, axonal degeneration, and stem cell biology, respectively. The goal of this proposal is to determine how genomic variants in tau that are associated with risk for tauopathies contribute to the development of these diseases using human iPSC-derived neurons. The overarching hypothesis of this proposal is that common mechanisms exist by which disease mutations and risk haplotypes disrupt tau metabolism and contribute to disease pathogenesis. To define these common mechanisms, I will measure several modalities of tau metabolism in iPSC-derived neurons from disease mutation and risk haplotype carriers. Through this research and mentored training plan, Dr. Karch will begin to define the molecular mechanisms underlying tauopathies and will establish new experimental tools and approaches that will form the foundation for a career as an independent, translational neuroscientist.