Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis

摘要 这项修订申请的标题是“成人急性损伤肺的再生 《人类干细胞》是扩大亲代资助范围的《建模、致病》 和治疗特发性肺纤维化的研究将进一步再生 通过开发治疗急性肺的成人干细胞疗法来加速药物的使用 受伤。我们建议的治疗方法是通过以下方式再生急性损伤的肺 靶向切除受损的肺上皮(同时保留肺血管 和周围实质组织)，随后交付IPSC来源的肺 细胞。家长奖助金和这项申请都是基于三个高度创新的 我们实验室最近开发的翻译技术：(I)大量数字的推导 成人IPSCs肺祖细胞的体外扩增，(Ii)体外肺的延长 通过常温交叉循环从6小时支持到3-5天，以及(3)非 用于实时监测细胞输送和肺组织的侵入性射频消融系统 再生。 为了达到最大的意义，我们关注急性肺病最常见的原因之一。 经常导致急性呼吸窘迫综合征的损伤--胃吸入 (ARDS)。为了最大限度地发挥翻译潜力，我们选择开发一种就地方法来 肺再生，在患者将进行介入性手术的情况下，通过 用治疗性人IPSC替代损伤区(S)的缺陷细胞 使用非常薄的、灵活的、成像引导的支气管镜检查肺细胞。我们会研究 在交叉循环和换气(超过3-5天)和在 在临床相关的猪模型中原位(超过1个月)，使用在 我们之前和初步的研究。该项目旨在为以下目的收集数据 为治疗急性肺损伤的I期人体试验准备IRB/FDA应用 在为期一年的资助结束时，使用治疗性的人IPSC来源的肺细胞。

ABSTRACT This revision application entitled “Regeneration of acutely injured lungs using adult human stem cells” is to expand the scope of the parent grant “Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis” into studies that will further regenerative medicine and accelerate its use by developing an adult stem cell therapy for acute lung injury. The treatment modality we propose is to regenerate acutely injured lungs by targeted removal of damaged pulmonary epithelium (while preserving lung vasculature and surrounding parenchymal tissue), followed by delivery of iPSC-derived pulmonary cells. Both the parent grant and this application are based on three highly innovative translational technologies recently developed in our labs: (i) derivation of large numbers of pulmonary progenitors from adult human iPSCs, (ii) prolongation of ex vivo lung support from 6 hours to 3–5 days by normothermic cross-circulation, and (iii) a non- invasive theranostic system for real-time monitoring of cell delivery and lung regeneration. For maximal significance, we focus on one of the most common causes of acute lung injury - gastric aspiration - that frequently leads to acute respiratory distress syndrome (ARDS). For maximal translational potential, we chose to develop an in-situ approach to lung regeneration, where an interventional procedure will be performed in the patient, by replacing defective cells in the region(s) of injury with therapeutic human iPSC-derived pulmonary cells using a very thin, flexible, imaging-guided bronchoscope. We will study lung regeneration ex vivo under cross-circulation and ventilation (over 3–5 days) and in situ (over 1 month) in a clinically relevant porcine model, using protocols established in our previous and preliminary studies. The project is designed to collect data for preparing the IRB/FDA applications for Phase I human trials to treat acute lung injury with therapeutic human iPSC-derived pulmonary cells by the end of the 1-year grant.