GENETIC DISRUPTION OF TAU METABOLISM IN TAUOPATHIES

描述(由申请者提供)：本研究和培训计划的总体目标是确定自闭症的分子机制。Tau聚集物是tauopathy病的标志性病理特征，包括阿尔茨海默病、进行性核上性瘫痪、额颞叶痴呆、皮质基底膜变性和Pick病。虽然帕金森氏病通常不是一种互补性疾病，但常见的tau基因(MAPT)单倍型是疾病的既定危险因素。这个项目旨在定义tau病潜在的分子机制，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Celust KArch博士将接受干细胞生物学、基因组学和轴突成像方面的高级培训，以支持一种创新的方法，该方法建立新的细胞模型，使用人类诱导多能干细胞(IPSC)来源的神经元、锌指核酸酶和轴突成像来研究编码tau蛋白的MAPT基因变化在多大程度上扰乱tau病的tau代谢。被选为此次培训的导师是Alison Goate博士、Marc Diamond、Jeffrey Milbrandt和Yadong Huang，他们分别是人类和分子遗传学、tau聚集、轴突变性和干细胞生物学领域的国际公认专家。这项提议的目标是利用人类IPSC来源的神经元来确定tau基因中与tauopathy风险相关的基因组变异如何有助于这些疾病的发展。这一建议的主要假设是，存在疾病突变和风险单倍型扰乱tau代谢并促进疾病发病的共同机制。为了确定这些共同的机制，我将测量来自疾病突变和风险单倍型携带者的IPSC来源神经元中tau代谢的几种形式。通过这项研究和有指导的培训计划，卡奇博士将开始定义肌萎缩侧索硬化症的分子机制，并将建立新的实验工具和方法，为成为一名独立的转化型神经科学家奠定基础。

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.