Molecular drivers of tauopathies in stem cell models from diverse human populations

不同人群干细胞模型中tau蛋白病的分子驱动因素

• 批准号: 10724049
• 负责人: Miguel Minaya
• 金额: $ 12.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724049
• 关键词: Affect; African; African American population; Asian; Asian Americans; Binding; Biology; Brain; Brazil; C-terminal; CRISPR interference; CRISPR screen; Calcium; Categories; Cell Line; Cell model; Collection; Communities; Coupled; Data; Disease; Dominant Genes; Engineering; European; European ancestry; Exons; Foundations; Frontotemporal Lobar Degenerations; Functional disorder; Gene Silencing; Genes; Genetic; Genetic Risk; Genome engineering; Genomic approach; Genomics; Goals; Homeostasis; Human; Human Genetics; Induced pluripotent stem cell derived neurons; Inherited; International; Japan; MAPT gene; Maps; Mentors; Molecular; Molecular Genetics; Molecular Profiling; Mutation; Neurodegenerative Disorders; Neurons; Nigeria; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Population Heterogeneity; Postdoctoral Fellow; Process; RNA Splicing; Research; Research Personnel; South American; Synapses; Tauopathies; Techniques; Therapeutic Intervention; Toxic effect; Training; Translating; Work; career; clinical application; donor stem cell; functional genomics; genome editing; induced pluripotent stem cell; innovation; molecular drug target; neuron development; new therapeutic target; novel; programs; proteostasis; screening; stem cell biology; stem cell model; tau Proteins; therapeutic target; tool; transcriptome sequencing; transcriptomics

Project Summary/Abstract The overall goal of this research and training plan is to define the molecular mechanisms underlying tauopathies in diverse populations. Currently, the contribution of specific MAPT mutations to tau toxicity, the mechanisms by which tauopathies occur, and the contribution of different genetic backgrounds to these mechanisms remain poorly understood. This project aims to define druggable molecular signatures of MAPT mutations using stem cell models from African (Nigeria), Asian (Japan), and South American (Brazil) populations. The investigator, Dr. Miguel Minaya, will gain advanced training in stem cell biology and functional genomics in support of an innovative approach that establishes novel cell models that use human induced pluripotent stem cell (iPSC)-derived neurons, diverse populations, and CRISPR-based screens to study the extent to which MAPT mutations occurring in diverse genetic backgrounds will produce common and/or unique molecular signatures of disease. The mentors who were selected for this training, Drs. Celeste Karch, Carlos Cruchaga, and Martin Kampmann, are internationally recognized experts in the fields of tau biology, human and molecular genetics, stem cell biology, genome editing, and functional genomic screens using CRISPRi. The goal of this proposal is to define druggable molecular signatures of MAPT mutations using stem cell models from diverse populations. The overarching hypothesis of this proposal is that MAPT mutations occurring in diverse genetic backgrounds will produce common molecular signatures of disease. To define these common mechanisms, I will define molecular changes in iPSC-derived neurons from iPSC lines with engineered MAPT mutations and will then functionally annotate those genes using CRISRPi screens. Through this research and mentored training plan, Dr. Minaya will make fundamental contributions to our knowledge of the mechanisms by which disruptions in the MAPT gene are associated with tauopathies and will establish new experimental tools and approaches that will form the foundation for a career as an independent, translational neuroscientist.

项目总结/摘要 这项研究和培训计划的总体目标是确定潜在的分子机制 不同人群中的tau蛋白病。目前，特异性MAPT突变对tau毒性的贡献， tau蛋白病发生的机制，以及不同遗传背景对这些疾病的影响。 机制仍然知之甚少。该项目旨在定义MAPT的可药用分子特征 使用来自非洲（尼日利亚）、亚洲（日本）和南美（巴西）的干细胞模型进行突变 人口。 研究人员米格尔米纳亚博士将在2010年获得干细胞生物学和功能基因组学方面的高级培训。 支持一种创新方法，建立使用人类诱导多能干细胞的新型细胞模型 细胞（iPSC）衍生的神经元，不同的群体，和基于CRISPR的屏幕，以研究在何种程度上， 在不同遗传背景中发生的MAPT突变将产生共同和/或独特的分子生物学效应。 疾病的标志。被选中参加这次培训的导师是塞莱斯特·卡奇博士、卡洛斯·克鲁查加博士、 和马丁·坎普曼，是国际公认的tau生物学、人类和分子生物学领域的专家。 遗传学、干细胞生物学、基因组编辑和使用CRISPRi的功能性基因组筛选。 这项提案的目标是利用干细胞技术来定义MAPT突变的药物分子特征。 来自不同人群的模型。这项提议的首要假设是MAPT突变 在不同的遗传背景下发生的疾病将产生共同的疾病分子特征。以限定 这些共同的机制，我将定义iPSC衍生的神经元从iPSC线的分子变化， 工程化的MAPT突变，然后使用CRISRPi筛选功能注释这些基因。通过 这项研究和指导培训计划，米纳亚博士将作出根本性的贡献，我们的知识， MAPT基因的破坏与tau蛋白病相关的机制， 实验工具和方法，将形成作为一个独立的，翻译的职业生涯的基础， 神经学家