Frontotemporal Dementia Induced Pluripotent Stem Cell Consortium

描述（由申请方提供）：我们建议建立一个全面、经验证的成人皮肤成纤维细胞和人诱导多能干细胞（hiPSC）系的储存库，这些细胞系来自具有遗传定义突变的额颞叶痴呆（FTD）患者和家族性非突变携带对照。hiPSC在开发用于研究相关人类细胞类型（如人类神经元）中疾病发病机制的体外FTD模型方面具有巨大的前景，否则无法获得这些模型。我们将使用一种成熟的、协作的、多机构方法，从携带目前已知引起FTD的常见基因突变的FTD患者中建立成人皮肤成纤维细胞库：tau（MAPT）、C9ORF72和颗粒蛋白前体（GRN）。在目标1中，我们将招募具有确定基因突变的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 分子表型在目标2中，我们将通过我们最近取得成功的非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报告细胞系，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，以便我们可以精确区分突变特异性表型与个体间变异性的噪音。在目标3中，我们将衍生和验证人神经元，以在培养物中建模和研究FTD发病机制，并为FTD研究和药物开发提供具有稳健表型的hiPSC细胞系。基于我们以前在RNA和Tau生物学和病理生理学方面的研究经验，我们将专注于在C9ORF72和MAPT突变中具有GGGGCC重复扩增的人类神经元。所有细胞系将储存在Coriell研究所，并可供全球FTD研究和药物开发社区使用。这些资源应该通过加速发现来显著改变FTD的研究格局。

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.