Pluripotent stem cell modeling of children's interstitial lung disease

儿童间质性肺疾病的多能干细胞建模

基本信息

  • 批准号:
    9190619
  • 负责人:
  • 金额:
    $ 2.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary Alveolar type II cell (AEC2) dysfunction has been implicated as a primary cause of pathogenesis in many poorly understood lung diseases that lack effective therapeutics. Childhood interstitial lung disease (chILD) is a group of monogenic diseases of the AEC2, which can be caused by autosomal dominant mutations in the surfactant protein C (SFTPC) gene. These mutations are classified based on their location in the pro-SFTPC protein as BRICHOS or non-BRICHOS, and may result in protein misfolding and aggregation, impaired lipid metabolism, ER stress, and ultimately apoptosis in AEC2s. AEC2s are inaccessible to study in the developing human embryo and difficult to study in infants/children. They proliferate poorly and rapidly differentiate into other cell types when isolated and cultured. Generating AEC2s de novo using induced pluripotent stem cell (iPSC) technology would provide the first opportunity to study diseases of the alveolar epithelium in-vitro, including SFTPC mutations. Individuals carrying SFTPC mutations are believed to be susceptible to lung disease due to two distinct pathogenic processes initiated in AEC2s, both of which can be mechanistically interrogated in disease-specific iPSC-derived AEC2s (iAEC2s). We hypothesize that BRICHOS SFTPC mutations will induce upregulation of all three canonical UPR pathways in iAEC2s, leading to apoptosis, whereas non-BRICHOS mutations will result in to mistrafficked surfactant protein aggregates in endosomes and at the plasma membrane, leading to dysfunctional surfactant metabolism. This hypothesis will be tested in two specific aims. In aim 1, we will use transcription activator-like effector nucleases (TALENs) to target the AEC2 lineage-specific SFTPC locus of human iPSC lines with a fluorescent reporter gene. This will enable the first ever isolation of a pure population of patient-specific iAEC2s after lung epithelial differentiation. In aim 2, we will target wild type and mutant GFP/SFTPC fusion genes into the SFTPC locus of patient-derived iPSC lines, thereby engineering a novel model system for real time visualization of pathogenic processes responsible for AEC2 toxicity due to protein mistrafficking in iAEC2s with SFTPC mutations. Ultimately, we intend to use iAEC2s from patients with SFTPC mutations to perform an in-vitro screen for therapeutics that may ameliorate mistrafficking and ER stress. Completion of these aims would represent the first critical steps towards achieving our long term goal of developing clinically applicable in vitro models able to predict personalized responses to drug therapies for the patients from whom the iPSCs were derived.
项目摘要 肺泡II型细胞(AEC 2)功能障碍已被认为是许多疾病发病机制的主要原因。 缺乏有效治疗方法的肺部疾病。儿童间质性肺病(child)是一种 AEC2的单基因疾病组,其可由AEC2中的常染色体显性突变引起。 表面活性蛋白C(SFTPC)基因。这些突变基于它们在pro-SFTPC中的位置进行分类。 蛋白质作为BRICHOS或非BRICHOS,并可能导致蛋白质错误折叠和聚集, 代谢、ER应激和最终凋亡。在发展中国家, 人类胚胎和难以在婴儿/儿童中研究。它们的增殖能力很差, 其他类型的细胞分离和培养。使用诱导多能干细胞从头产生AEC 2 (iPSC)技术将首次提供在体外研究肺泡上皮疾病的机会, 包括SFTPC突变。携带SFTPC突变的个体被认为易患肺结核。 由于AEC 2中启动的两种不同的致病过程而引起的疾病,这两种过程都可以是机械性的, 在疾病特异性iPSC衍生的AEC 2(iAEC 2)中询问。我们假设BRICHOS SFTPC 突变将诱导iAEC 2中所有三种典型UPR途径的上调,导致细胞凋亡, 而非BRICHOS突变将导致内体中表面活性剂蛋白聚集体的错误表达 和质膜,导致功能失调的表面活性剂代谢。这一假设将在 两个具体目标。在目标1中,我们将使用转录激活因子样效应物核酸酶(TALEN)来靶向 具有荧光报告基因的人iPSC系的AEC 2谱系特异性SFTPC基因座。这将使 在肺上皮分化后首次分离出患者特异性iAEC 2的纯群体。在目标2中, 我们将野生型和突变型GFP/SFTPC融合基因靶向患者来源的iPSC的SFTPC基因座, 线,从而设计用于致病过程的真实的时间可视化的新模型系统 在具有SFTPC突变的iAEC 2中,由于蛋白质误扩增,导致AEC 2毒性。最终我们 打算使用来自SFTPC突变患者的iAEC 2进行体外筛选, 可以改善误射和ER应激。完成这些目标将是第一个关键步骤 为了实现我们的长期目标,开发临床适用的体外模型, 这些iPSC来源于患者对药物治疗的个性化反应。

项目成果

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