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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的此修订申请名为“使用成人的急性伤害肺部再生人类干细胞”是为了扩大父授予的范围“建模，发病机理以及将特发性肺纤维化的处理”将进一步再生的研究药物并通过开发成人干细胞疗法来加速其使用急性肺受伤。我们建议的治疗方式是通过靶向去除受损的肺上皮（同时保存肺脉管系统和周围的实质组织），然后递送IPSC衍生的肺细胞。父母赠款和此应用程序都是基于三个高度创新的转化技术最近在我们的实验室中开发：（i）大量的推导成人人IPSC的肺祖细胞，（ii）体内肺的延长通过正常热交叉循环从6小时到3-5天，（iii）非 - 用于实时监测细胞递送和肺的侵入性治疗系统再生。为了获得最大的意义，我们专注于急性肺最常见的原因之一伤害 - 胃抽吸 - 经常导致急性呼吸窘迫综合征（ARDS）。为了获得最大的翻译潜力，我们选择开发一种原位方法肺部再生，在患者中将在患者中进行介入程序用治疗性人IPSC衍生的损伤区域中替换有缺陷的细胞肺细胞使用非常薄，柔性，成像引导的支气管镜。我们将学习在交叉循环和通风下（超过3-5天）和在使用在临床相关的猪模型中的原位（超过1个月），使用建立的方案我们以前的和初步研究。该项目旨在收集数据为I期人类试验准备IRB/FDA申请以治疗急性肺损伤在1年赠款的结束之前，使用治疗性人IPSC衍生的肺细胞。