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.

项目概要/摘要 该研究和培训计划的总体目标是定义潜在的分子机制 不同人群中的tau蛋白病。目前，特定 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的贡献 机制仍知之甚少。该项目旨在定义 MAPT 的可成药分子特征 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 Miguel Minaya 博士将在以下国家接受干细胞生物学和功能基因组学方面的高级培训： 支持建立使用人类诱导多能干细胞的新型细胞模型的创新方法 细胞 (iPSC) 衍生的神经元、不同群体和基于 CRISPR 的筛选来研究 发生在不同遗传背景中的 MAPT 突变将产生共同和/或独特的分子 疾病的特征。被选参加本次培训的导师，博士。塞莱斯特·卡奇、卡洛斯·克鲁查加、 和 Martin Kampmann 是 tau 生物学、人类和分子领域的国际公认专家 使用 CRISPRi 进行遗传学、干细胞生物学、基因组编辑和功能基因组筛选。 该提案的目标是使用干细胞定义 MAPT 突变的可药物分子特征 来自不同人群的模型。该提案的总体假设是 MAPT 突变 发生在不同的遗传背景中将产生共同的疾病分子特征。定义 这些常见机制，我将定义来自 iPSC 系的 iPSC 衍生神经元的分子变化 设计 MAPT 突变，然后使用 CRISRPi 筛选对这些基因进行功能注释。通过 通过这项研究和指导培训计划，Minaya 博士将为我们的知识做出根本性贡献 MAPT 基因破坏与 tau 蛋白病相关的机制将建立新的机制 实验工具和方法将为独立、转化的职业生涯奠定基础 神经科学家。