Frontotemporal Dementia Induced Pluripotent Stem Cell Consortium

额颞叶痴呆诱导的多能干细胞联盟

基本信息

批准号：
8506482
负责人：
Fen-Biao Gao
金额：
$ 75.16万
依托单位：
J. DAVID GLADSTONE INSTITUTES
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：
2013-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506482
关键词：
Adult Animal Model Autopsy Award Awareness Biology Biopsy C9ORF72 California Cell Line Charge Collaborations Collection Communities Complex Consultations DNA-Binding Proteins Dermal Development Disease Disease model Empathy Family member Fibroblasts Freezing Frontotemporal Dementia Functional disorder Funding Gene Mutation Generations Genes Goals Grant Human In Vitro Individual Inherited Institutes Language Link Massachusetts Mediating Medical center Methodology Monitor Multivesicular Body Mutation Neurodegenerative Disorders Neuronal Differentiation Neurons Noise Pathogenesis Patients Phenotype Progranulin Progressive Supranuclear Palsy Prosencephalon Proteins Protocols documentation RNA Recruitment Activity Regenerative Medicine Reporter Research Research Infrastructure Research Personnel Resources San Francisco Skin Staging Standardization Study models Technology Testing Tissues Universities Zinc Fingers base brain tissue cell bank cell type disease characteristic disease phenotype drug development drug discovery end stage disease experience induced pluripotent stem cell insight molecular phenotype mouse model nuclease public health relevance repository research and development research clinical testing social success tau Proteins therapeutic target trait ubiquilin valosin-containing protein

项目摘要

DESCRIPTION (provided by applicant): We propose to establish a comprehensive, validated repository of adult human dermal fibroblasts and human induced pluripotent stem cell (hiPSC) lines from frontotemporal dementia (FTD) patients with genetically defined mutations and familial, non-mutation carrying controls. hiPSCs hold tremendous promise for the development of in vitro FTD models for studying disease pathogenesis in relevant human cell types that would otherwise be impossible to obtain, such as human neurons. Using an established, collaborative, multi- institutional approach, we will bank adult human dermal fibroblasts from FTD patients carrying common mutations in the genes currently known to cause FTD: tau (MAPT), C9ORF72, and progranulin (GRN). In Aim 1, we will recruit both FTD patients with defined genetic mutations and control subjects. Comprehensive and longitudinal clinical evaluations will be linked to each cell line, allowing us to correlate disease characteristics with molecular phenotypes. In Aim 2, we will reprogram fibroblasts into hiPSCs by non-DNA-integrating technologies with which we have had recent success. In addition, we will further create EGFP reporter lines for monitoring and standardizing differentiation protocols in FTD-relevant cell types such as forebrain neurons. We will also correct selective mutations to create isogenic control lines so that we can precisely differentiate mutation-specific phenotypes from the noise of inter-individual variability. In Aim 3, we will derive and validate human neurons to model and study FTD pathogenesis in culture and to deliver hiPSC lines with robust phenotypes for FTD research and drug development. Based on our previous research experience in RNA and Tau biology and pathophysiology, we will focus on human neurons with GGGGCC repeat expansions in C9ORF72 and MAPT mutations. All cell lines will be banked at the Coriell Institute and will be accessible to the worldwide FTD research and drug development community. These resources should significantly alter the FTD research landscape by accelerating discovery.

描述（由申请人提供）：我们建议建立一个全面、经过验证的成人皮肤成纤维细胞和人类诱导多能干细胞（hiPSC）系的储存库，这些细胞系来自额颞叶痴呆（FTD）患者，这些患者具有遗传定义的突变和家族性非突变携带对照。 hiPSC 对于开发体外 FTD 模型具有巨大的前景，该模型可用于研究相关人类细胞类型（例如人类神经元）的疾病发病机制，否则这些模型是不可能获得的。使用已建立的、协作的、多机构的方法，我们将储存来自 FTD 患者的成人真皮成纤维细胞，这些患者携带目前已知导致 FTD 的常见基因突变：tau (MAPT)、C9ORF72 和颗粒体蛋白前体 (GRN)。在目标 1 中，我们将招募具有明确基因突变的 FTD 患者和对照受试者。全面和纵向的临床评估将与每个细胞系相关联，使我们能够将疾病特征与分子表型。在目标 2 中，我们将通过最近取得成功的非 DNA 整合技术将成纤维细胞重编程为 hiPSC。此外，我们将进一步创建 EGFP 报告基因系，用于监测和标准化 FTD 相关细胞类型（如前脑神经元）的分化方案。我们还将纠正选择性突变以创建同基因对照系，以便我们能够精确地区分突变特异性表型与个体间变异的噪音。在目标 3 中，我们将衍生并验证人类神经元，以在培养物中模拟和研究 FTD 发病机制，并为 FTD 研究和药物开发提供具有强大表型的 hiPSC 系。基于我们之前在 RNA 和 Tau 生物学和病理生理学方面的研究经验，我们将重点关注 C9ORF72 和 MAPT 突变中具有 GGGGCC 重复扩展的人类神经元。所有细胞系都将储存在 Coriell 研究所，并可供全球 FTD 研究和药物开发界使用。这些资源将通过加速发现来显着改变 FTD 研究格局。