Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis

特发性肺纤维化的建模、发病机制和治疗

• 批准号: 9516638
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 27.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9516638
• 关键词: Acute; Acute Lung Injury; Address; Adult; Adult Respiratory Distress Syndrome; Affect; Animals; Benchmarking; Biomedical Engineering; Blood Vessels; Bronchoscopes; Cell Therapy; Cells; Cellular biology; Chest; Clinical; Clinical Research; Clinical Treatment; Cross Circulation; Data; Derivation procedure; Development; Distal; Dose; Engraftment; Environmental air flow; Epithelial Cells; Epithelium; Evaluation; Excision; Extracorporeal Membrane Oxygenation; Family suidae; Functional disorder; Funding; Gases; Goals; Grant; Hamman-Rich syndrome; Health; Histology; Hour; Human; Imaging technology; In Situ; In Vitro; Inflammation; Injury; Institution; Intervention; Joints; Label; Lead; Long-Term Effects; Lung; Lung Compliance; Lung Transplantation; Lung diseases; Maintenance; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Natural regeneration; Operative Surgical Procedures; Organoids; Outcome; Pathogenesis; Patients; Phase; Phenotype; Population; Preparation; Procedures; Protocols documentation; Publications; Real-Time Systems; Recording of previous events; Recovery; Regenerative Medicine; Replacement Therapy; Research Personnel; Respiratory physiology; Safety; Stomach; Support System; Supporting Cell; Technology; Therapeutic; Thinness; Time; Tissue Model; Tissues; Treatment Efficacy; Validation; Vascular Endothelium; Vascular resistance; adult stem cell; base; clinically relevant; design; dosage; flexibility; healing; human adult stem cell; image guided; imaging modality; imaging platform; induced pluripotent stem cell; injured; innovation; insight; lung imaging; lung preservation; lung regeneration; mortality; non-invasive monitor; novel; parent grant; progenitor; targeted treatment; theranostics; therapeutic evaluation; transcriptome sequencing

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.

摘要 本修订申请题为“使用成人肺再生急性损伤的肺”， 人类干细胞”是扩大范围的父母补助金“建模，发病机制 和治疗特发性肺纤维化”的研究，将进一步再生 通过开发成人干细胞疗法治疗急性肺疾病， 损伤我们提出的治疗方式是通过以下方法使急性损伤的肺再生： 靶向去除受损的肺上皮（同时保留肺脉管系统 和周围的实质组织），然后递送iPSC衍生的肺细胞。 细胞父母补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）大量的推导 （ii）来自成年人iPSC的肺祖细胞的离体肺祖细胞生长的延长， 支持从6小时到3-5天的正常体温交叉循环，和（iii）非- 用于实时监测细胞递送和肺侵入性治疗诊断系统 再生 为了获得最大的意义，我们将重点放在急性肺损伤最常见的原因之一， 损伤-胃吸入-经常导致急性呼吸窘迫综合征 （急性呼吸窘迫综合征）。为了获得最大的翻译潜力，我们选择开发一种原位方法， 肺再生，其中将在患者中进行介入手术，通过 用治疗性人iPSC衍生的细胞替换损伤区域中的缺陷细胞 肺细胞使用非常薄，灵活，成像引导支气管镜。我们将研究 在交叉循环和通气下离体肺再生（超过3-5天）和 在临床相关猪模型中原位（超过1个月），使用 我们之前和初步的研究。该项目旨在收集数据， 为治疗急性肺损伤的I期人体试验准备IRB/FDA申请 在1年资助期结束前，用治疗性人类iPSC衍生的肺细胞。