GENETIC DISRUPTION OF TAU METABOLISM IN TAUOPATHIES

TAU 病中 TAU 代谢的基因破坏

基本信息

批准号：
9404951
负责人：
Celeste Marie Karch
金额：
$ 11.37万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9404951
关键词：
Affect Alternative Splicing Alzheimer&apos s Disease Amyloid beta-Protein Biochemical Biochemistry Biological Models Biology Brain Cell model Cells Complex Development Diamond Disease Event Exogenous Factors Expression Profiling Foundations Frontotemporal Dementia Genes Genetic Genetic Polymorphism Genetic Risk Genomics Goals Haplotypes Human Human Genetics Image Imaging Techniques International Lead MAPT gene Measures Mentors Metabolism Modality Modeling Molecular Molecular Genetics Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Pathogenesis Pathologic Pathology Phenotype Phosphorylation Physiological Pick Disease of the Brain Population Progressive Supranuclear Palsy Protein Isoforms Proteins RNA Splicing Regulation Research Research Personnel Research Training Risk Risk Factors Role Tauopathies Techniques Therapeutic Intervention Training axonal degeneration career corticobasal degeneration disorder risk genetic variant improved induced pluripotent stem cell innovation mouse model mutation carrier neuron loss novel public health relevance risk variant stem cell biology tau Proteins tau aggregation tool zinc finger nuclease

项目摘要

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.

描述（由申请人提供）：本研究和培训计划的总体目标是定义功的分子机制。 tau骨料是tauopathies的标志性病理特征，包括阿尔茨海默氏病，进行性性次核麻痹，额颞痴呆，皮质性脂肪性变性和Pick的疾病。虽然帕金森氏病通常不会被描述为陶氏病，但常见的tau基因（MAPT）单倍型是疾病的确定危险因素。该项目旨在定义双性疾病的分子机制，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。 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陶氏病中的代谢。被选为这项培训的导师。 Alison Goate，Marc Diamond，Jeffrey Milbrandt和Yadong Huang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知名专家。该提案的目的是确定与扭曲风险相关的TAU基因组变异如何使用人IPSC衍生的神经元有助于这些疾病的发展。该提议的总体假设是存在共同的机制，即疾病突变和风险单倍型破坏TAU代谢并导致疾病发病机理。为了定义这些常见的机制，我将通过疾病突变和风险单倍型载体中的IPSC衍生神经元中TAU代谢的几种方式。通过这项研究和指导的培训计划，Karch博士将开始定义双性恋疗法的分子机制，并将建立新的实验工具和方法，为作为独立的，转化的神经科学家的职业奠定基础。