Frontotemporal Dementia Induced Pluripotent Stem Cell Consortium

描述（由申请人提供）：我们建议建立一个全面的、经过验证的成人真皮成纤维细胞和人类诱导多能干细胞（hiPSC）细胞系的存储库，这些细胞系来自具有基因定义突变和家族性、非突变携带对照的额颞叶痴呆（FTD）患者。hipsc对体外FTD模型的发展有着巨大的希望，用于研究相关人类细胞类型（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。使用一种已建立的、合作的、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，这些成纤维细胞携带目前已知的导致FTD的常见基因突变：tau （MAPT）、C9ORF72和前颗粒蛋白（GRN）。在Aim 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联系起来，使我们能够将疾病特征与

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.