Subzero Non-freezing preservation of whole mammalian organisms

整个哺乳动物有机体的零下非冷冻保存

• 批准号: 10705577
• 负责人: Korkut Uygun
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705577
• 关键词: Air; Alkanes; Applications Grants; Area; Birth; Brain; Breathing; Carbohydrates; Caring; Cells; Data; Diapause; Endothelium; Environment; Extracorporeal Membrane Oxygenation; Formulation; Freezing; Funding Mechanisms; Goals; Grant; Heart; Hemoglobin; Hibernation; Histologic; Hour; Human; Ice; Immersion; Individual; Injury; Intestines; Ischemia; Kidney; Liquid substance; Literature; Liver; Lung; Mammals; Medicine; Metabolic; Methods; Mission; Modeling; Molecular; Monitor; Mucous body substance; Mus; Muscle; National Institute of General Medical Sciences; Nature; Neonatal; Oils; Operative Surgical Procedures; Organ; Organism; Oxygen; Pathway interactions; Perfusion; Phase Transition; Phenotype; Physiological; Planet Mars; Probability; Protocols documentation; Race; Rattus; Recovery; Research; Research Project Grants; Resuscitation; Rewarming; Risk; Saline; Site; Skin; Societies; Suspensions; Techniques; Technology; Temperature; Testing; Thermodynamics; Thigh structure; Time; Tissues; Trauma; Variant; Vial device; Water; Whole Organism; animation; body cavity; crosslink; design; feasibility testing; gastrointestinal; inhibitor; innovation; interest; mouse model; natural hypothermia; neonatal mice; neonate; new technology; novel; postnatal; preservation; programs; public health relevance; sealant; success; technology development

ABSTRACT Realizing suspended animation for humans would be transformative for the society: in long term applications where months of preservation is needed, it would enable planetary missions to Mars and beyond. In the more immediate uses it could be enabling for delayed resuscitation purposes in certain cases. Extended suspended animation is commonly observed in nature including several mammalian species which hibernate at subzero environments with ambient temperature as low as -30 ºC. While such high subzero temperatures (defined here as 0 ºC to -30 ºC) is utilized commonly by nature as a means to establish whole organism preservation for extended durations, subzero non-freezing preservation has not been explored for mammalians in literature (see Significance) and remain a profitable area for research. Our overarching goal is to push the boundaries of scientific discovery by enabling metabolic stasis and reanimation for an organism without the natural capacity for suspended animation. The objective of this NIGMS exploratory research grant for technology development is to test the viability of sub-zero, non-freezing (SZNF) storage of a mammal for the first time in literature. The studies would also lead to preliminary data in a context where none exists, which in turn would enable continuation with a more traditional funding mechanism once the risks are reduced and mechanistic targets are identified to enable hypothesis driven research. This objective was formulated based on our team's prior success in scaling subzero nonfreezing preservation to human livers, which provided us with key new technologies enabling control of intracellular carbohydrate levels, understanding of endothelial sensitivity to ischemia and strategies for mitigation, and machine-assisted recovery/reanimation techniques to ameliorate preservation injury. However, the transition from a single organ to an entire mammalian organism presents a vertical step forward, a potential breakthrough but with considerable risk. As such, this technology design-directed proposal specifically matches the program requirements for this exploratory grant mechanism. As a result of these studies, we expect to develop novel technologies that enables preservation of neonatal and post- natal mice in subzero temperatures. To do so, we aim to develop several novel protocols and cryopreservatives to avoid freezing in the context of whole-organism storage. These results are expected to lead to preliminary data that shows survival after days of subzero storage, which will motivate future research, as well as key data that will enable formulation of new hypotheses that will enable the utilization of more traditional funding mechanisms.

摘要 实现人类的假死将对社会产生变革：在长期应用中， 如果需要数月的保存，它将使火星和更远的行星任务成为可能。在更直接的使用中， 在某些情况下可以实现延迟复苏的目的。延长的假死状态通常 在自然界中观察到，包括几种哺乳动物，它们在零度以下的环境中冬眠， 温度低至-30 ° C。虽然通常使用这种高的零度以下温度（在此定义为0 ºC至-30 ºC）， 自然作为一种手段，建立整个生物体保存延长时间，零度以下非冷冻保存 在文学作品中还没有探索过马里亚人（见意义），仍然是一个有利可图的研究领域。 我们的首要目标是通过实现代谢停滞和复苏来推动科学发现的边界 对于一个没有假死能力的生物体来说NIGMS探索性研究的目的是 技术开发赠款是为了测试零度以下，非冷冻（SZNF）储存哺乳动物的可行性， 第一次在文学这些研究还将在没有初步数据的情况下产生初步数据，而这反过来又将 一旦风险降低， 识别以实现假设驱动的研究。这一目标是根据我们团队先前在以下方面的成功制定的： 将零度以下的非冷冻保存扩大到人类肝脏，这为我们提供了关键的新技术， 细胞内碳水化合物水平，了解内皮对缺血的敏感性和缓解策略， 机器辅助恢复/复苏技术，以改善保存损伤。然而，从单一的 将一个器官移植到整个哺乳动物机体上，这是一个垂直的进步，是一个潜在的突破，但也有相当大的困难。 风险因此，这项技术设计指导的建议，特别符合该探索性的计划要求， 资助机制 作为这些研究的结果，我们希望开发新的技术，使新生儿和后， 纳塔尔小鼠在零度以下的温度下。为此，我们的目标是开发几种新的方案和冷冻保存剂，以避免 在整个有机体储存的情况下冷冻。这些结果预计将导致初步数据显示， 在零度以下储存数天后的存活率，这将激励未来的研究，以及使配方能够实现的关键数据。 新的假设，这将使利用更传统的筹资机制。