High subzero preservation of liver for transplantation

移植用肝脏的高度低温保存

基本信息

批准号：
10220401
负责人：
Mehmet Toner
金额：
$ 55.11万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-17 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220401
关键词：
Address Animals Antioxidants Bacteria Bioenergetics Blood Circulation Blood Vessels Cell Survival Cells Cellular Morphology Charge Chimerism Citric Acid Cycle Data Endothelial Cells Endothelium Engineering Exhibits Extracellular Space Fatty Acids Freezing Funding Glutathione Hour Human Ice Injury Legal patent Length Liver Location Measures Metabolic Methods Microscopic Modeling Molecular Movement Nature Operative Surgical Procedures Organ Organ Donor Organ Preservation Organ Transplantation Oxygen Patients Perfusion Permeability Protocols documentation Public Health Rana Rattus Recovery Reperfusion Injury Research Rodent Signal Transduction System Technology Temperature Time Tissue Engineering Tissues Toxic effect Transplantation Trehalose Vascular Endothelium Vascular resistance Viscosity Waiting Lists Wood material animation base cell injury cold temperature cost experience extracellular improved inhibitor/antagonist innovation ischemic injury liver preservation liver transplantation metabolomics organ injury oxidation point of injury preconditioning preservation prevent programs public health relevance scale up shear stress success transcriptome sequencing vascular injury wasting

项目摘要

ABSTRACT With more than five times the number of patients on the wait list than will receive a donor organ in the USA, the field of transplantation is facing a serious donor shortage crisis. Despite decades of research, a major critical bottleneck is the current preservation times for whole organs are limited to few hours of storage. Longer preservation times are required to enable global matching programs, eliminate unnecessary waste of organs, and reduce costs associated with unplanned surgeries, and are enabling for mixed-chimerism based tolerance induction protocols which require the donor organ to be kept viable for days so that recipient preconditioning can be done safely. Consequently, the focus of this application is to address a major unmet need in transplantation by prolonging the length of time organs can be kept in “suspended animation” ex vivo. Our approach is inspired by the hibernating and freeze-tolerant animals in nature. We aim to embrace and control the ice formation to achieve high subzero storage temperatures in the presence of extracellular ice, and storage durations of weeks to ultimately months. It is our hypothesis that the presence of ice in a non-injurious frozen state enables storage at lower temperatures (down to -30°C) and consequently a deeper metabolic stasis for weeks, while also enabling scale-up to human organs. In the previous funding period, we developed a new method to use ice nucleating bacteria to tightly control ice formation temperature and developed a partial freezing protocol down to -15°C that can store rat livers up to 5 days with ex vivo function, and also established a proof-of-concept in human livers. In this competing renewal application, we propose to build on our success and reach preservation temperatures down to -30°C, thus achieving suspended animation for weeks. We propose (i) to control ice formation in liver, which our prior studies demonstrated to be a key barrier; (ii) to develop targeted approaches to improve preservation of endothelium, which are at the interface of tissue and ice and are the first point of injury, and (iii) to develop a choreographed metabolic protocol to maximize ATP recovery and improve viability of the grafts for transplant.

抽象的在美国，等待名单上的患者数量是接受捐赠器官的患者数量的五倍多，尽管进行了数十年的研究，移植领域仍面临着严重的供体短缺危机。目前整个器官的保存时间仅限于几个小时，需要更长的保存时间。实现全球计划匹配，消除不必要的器官浪费，并降低与计划外相关的成本手术，并正在实现基于混合嵌合的耐受诱导方案，该方案要求供体器官保持存活数天，以便可以安全地完成接受者预处理，该应用的重点是通过延长器官“暂停”的时间来解决移植中未满足的主要需求我们的方法受到自然界中冬眠和耐冻动物的启发。并控制冰的形成，以在细胞外冰存在的情况下实现零度以下的高储存温度，并储存我们的假设是冰处于无害的冷冻状态。能够在较低温度（低至-30°C）下储存，从而使代谢停滞数周，同时还在上一个资助期间，我们开发了一种使用冰成核的新方法。细菌严格控制冰形成温度，并开发了一种低至 -15°C 的部分冷冻方案，可以将大鼠肝脏保存长达 5 天，并具有离体功能，并在人类肝脏中进行了概念验证。在竞争更新申请中，我们建议在我们的成功基础上再接再厉，将保存温度达到-30°C，因此，我们建议（i）控制肝脏中的冰形成，这是我们之前的研究。 (ii) 制定有针对性的方法来改善内皮细胞的保存，组织和冰的界面是第一个受伤点，并且（iii）开发精心设计的代谢方案最大限度地提高 ATP 恢复并提高移植物的活力。