Perpetual Organ Preservation and Rehabilitation (POPR)

永久器官保存和康复（POPR）

• 批准号: 10570609
• 负责人: Matthew Galen Hartwig
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570609
• 关键词: ATAC-seq; Biochemical; Biocompatible Materials; Biological; Biology; Biomedical Engineering; Blood Vessels; Cell Communication; Cells; Cellular biology; Clinical; Clinical Research; Consent; Country; Data; Development; Devices; Discipline; Disease; Endothelial Cells; Endothelium; Ensure; Environment; Epigenetic Process; Epithelium; Evaluation; Excision; Family suidae; Filtration; Health; Heart; Heart Diseases; Heart Research; Hematological Disease; Hour; Human; Individual; International; Intervention; Investigation; Kidney; Laboratories; Learning; Lung; Lung Transplantation; Lung diseases; Metabolic; Methods; Modeling; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Organ Viability; Outcome; Parenteral Nutrition; Pathology; Perfusion; Physiological; Physiology; Positioning Attribute; Preservation Technique; Process; Protocols documentation; Public Health; Publishing; Pulmonary Edema; Rehabilitation therapy; Reproducibility; Research; Research Personnel; Sleep Disorders; Small Intestines; Solid; Specialist; Specialized Center; Specimen; Structure of parenchyma of lung; Techniques; Technology; Testing; Time; Translational Research; Transplantation; Universities; Vascular Endothelium; Vascular resistance; Waste Products; Work; cell regeneration; clinical application; cost; experience; experimental study; immunoregulation; improved; in vivo; inflammatory marker; liver preservation; lung development; new technology; porcine model; pre-clinical; preclinical trial; preservation; programs; pulmonary artery endothelial cell; research study; respiratory; sample collection; single-cell RNA sequencing; small molecule therapeutics; success; transcriptomics; translational model; translational scientist; translational study

Project Summary/Abstract This R21 application for the NOSI: Bold New Bioengineering Research for Heart, Lung, Blood and Sleep Disorders and Diseases details the technical development of a unique method to maintain whole human lungs for an extended period in order to revolutionize solid organ transplantation and human translational research. Normothermic ex situ, or ex vivo, organ perfusion (EVOP) is a clinically accepted method of preserving, evaluating, and rehabilitating whole organs for transplantation. EVOP has also been utilized by scientists for translational research and emerged as an important platform to study organs with fully intact cell-cell interactions, endothelial and epithelial interfaces, and with the entire spectrum of cellular compartments seen in vivo. Therefore, EVOP provides a unique platform to preserve organs for transplantation, as well as to study human physiology and pathology through preclinical translational studies. Unfortunately, EVOP is currently severely limited due to the short time frame of organ health stability currently provided by the technology. Therefore, there is an unmet need in EVOP strategies that requires new technology. The investigative team has the needed experience in organ transplantation, pulmonary physiology, biomedical engineering and vascular biology in order to ensure success of the proposed work. Aim 1 will leverage the expertise of the investigators with a porcine model of lung EVOP to extended stable organ preservation to at least 5 days through several key technology advances, including metabolic substrate support, waste product removal, dual perfusion, and the use of cellular enriched perfusate. Porcine lungs were utilized extensively for the initial development of lung EVOP and provide a high-fidelity model for translational work. In Year 2, Aim 2 will leverage and validate lessons learned during Aim 1 using human lungs from consented organ donors. The overall objective of this proposal is to obviate the current limitation of time for lung EVOP by adapting existing ex vivo lung perfusion strategies to allow for perpetual organ preservation and rehabilitation, or POPR. POPR would radically change allocation and availability of organs, allow time for interventions that could rehabilitate otherwise unusable organs, improve organs via immunomodulation or microbiologic clearance, and potentially mitigate other factors that limit the use of potential organ donors. Therefore, the development of POPR would be of tremendous public health importance and our proposal leverages the transdisciplinary expertise of lung transplantation, organ preservation, vascular endothelial health and biomedical engineering specialists. The technology proposed herein, once developed, could be used by transplant programs clinically and by researchers in specialized centers across the country. Importantly, principals developed herein can be applied to other solid organs, including heart, kidney, and small bowel, to extend solid organ transplantation and research.

项目摘要/摘要 R21 NOSI的应用：大胆的心脏，肺，血液和睡眠的新生物工程研究 疾病和疾病详细介绍了一种保持整个人类肺的独特方法的技术发展 为了彻底改变固体器官移植和人类翻译研究。 正常热的原位或离体器官灌注（EVOP）是一种临床上可接受的保存方法 评估和修复整个器官进行移植。科学家还利用了evop 翻译研究并成为研究具有完全完整细胞相互作用的器官的重要平台， 内皮和上皮界面，以及在体内看到的整个细胞隔室。 因此，EVOP提供了一个独特的平台来保护器官进行移植以及研究人类 通过临床前翻译研究生理和病理学。不幸的是，Evop目前严重 由于该技术目前提供的器官健康稳定性的时间较短，因此受到限制。所以， EVOP策略的需求未满足，需要新技术。调查团队有 器官移植，肺部生理，生物医学工程和血管生物学所需的经验 为了确保拟议工作的成功。 AIM 1将利用调查人员的专业知识 通过几个密钥 技术进步，包括代谢底物支持，废物产品清除，双重灌注以及使用 富含细胞的灌注液。猪肺广泛用于肺EVOP的初步发展 并为翻译工作提供高保真模型。在第二年，AIM 2将利用和验证课程 在AIM 1期间，使用同意器官捐赠者的人类肺部学习。该提议的总体目标 通过适应现有的离体肺灌注来消除肺EVOP的当前时间限制 允许永久器官保存和康复的策略，或POPR。 Popr将在根本上 更改器官的分配和可用性，让时间进行干预措施，以便恢复原本 无法使用器官，通过免疫调节或微生物学清除改善器官，并有可能减轻 限制潜在器官捐献者使用的其他因素。因此，Popr的发展将是 巨大的公共健康重要性，我们的提议利用了肺的跨学科专业知识 移植，器官保存，血管内皮健康和生物医学工程专家。这 本文提出的技术曾经开发，可以在临床上和 全国专业中心的研究人员。重要的是，本文开发的校长可以应用 到其他固体器官，包括心脏，肾脏和小肠，以扩展固体器官移植和 研究。