[论文解读] A new pharmacological preconditioning-based target: from drosophila to kidney transplantation

Michel Tauc, Nicolas Mélis+4 more|arXiv (Cornell University)|Aug 9, 2019

Organ Transplantation Techniques and Outcomes被引用 4

一句话总结

本文在果蝇中鉴定出一种保守的药理性预处理通路，可增强对缺血再灌注性损伤的耐受性，成功将其转化至哺乳动物模型，并具有在肾移植中应用的潜力。该研究揭示了一对新颖的药物/靶点，可实现如器官移植等可预测手术环境中临床预处理，克服了机械性预处理的局限性，并满足了缺血性损伤保护方面的未被满足的临床需求。

ABSTRACT

One of the biggest challenges in medicine is to dampen the pathophysiological stress induced by an episode of ischemia. Such stress, due to various pathological or clinical situations, follows a restriction in blood and oxygen supply to tissue, causing a shortage of oxygen and nutrients that are required for cellular metabolism. Ischemia can cause irreversible damage to target tissue leading to a poor physiological recovery outcome for the patient. Contrariwise, preconditioning by brief periods of ischemia has been shown in multiple organs to confer tolerance against subsequent normally lethal ischemia. By definition, preconditioning of organs must be applied preemptively. This limits the applicability of preconditioning in clinical situations, which arise unpredictably, such as myocardial infarction and stroke. There are, however, clinical situations that arise as a result of ischemia-reperfusion injury, which can be anticipated, and are therefore adequate candidates for preconditioning. Organ and more particularly kidney transplantation, the optimal treatment for suitable patients with end stage renal disease (ESRD), is a predictable surgery that permits the use of preconditioning protocols to prepare the organ for subsequent ischemic/reperfusion stress. It therefore seems crucial to develop appropriate preconditioning protocols against ischemia that will occur under transplantation conditions, which up to now mainly referred to mechanical ischemic preconditioning that triggers innate responses. It is not known if preconditioning has to be applied to the donor, the recipient, or both. No drug/target pair has been envisioned and validated in the clinic. Options for identifying new target/drug pairs involve the use of model animals, such as drosophila, in which some physiological pathways, such as the management of oxygen, are highly conserved across evolution. Oxygen is the universal element of life existence on earth. In this review we focus on a very specific pathway of pharmacological preconditioning identified in drosophila that was successfully transferred to mammalian models that has potential application in human health. Very few mechanisms identified in these model animals have been translated to an upper evolutionary level. This review highlights the commonality between oxygen regulation between diverse animals.

研究动机与目标

• 鉴定在模式生物中赋予缺血耐受性的进化保守分子通路。
• 将果蝇中的药理活性预处理靶点转化至哺乳动物模型。
• 评估该靶点在肾移植临床应用中的潜力。
• 通过鉴定可药物靶向的靶点，克服机械性预处理的局限性。

提出的方法

• 利用果蝇作为模式生物，研究氧稳态调节与缺血应激反应。
• 鉴定出在细胞适应低氧与再氧合应激中起作用的保守通路。
• 在哺乳动物细胞与器官模型中（尤其是肾组织）验证该通路的功能。
• 评估靶通路的药理激活对缺血再灌注性损伤的保护作用。
• 探索在临床器官移植环境中基于药物的预处理的潜力。
• 比较药理性预处理与机械性缺血预处理在可行性与有效性方面的差异。

实验结果

研究问题

• RQ1 果蝇中哪些保守的分子通路介导了对缺血再灌注性损伤的保护作用？
• RQ2 靶向该通路的药理剂是否可在哺乳动物模型中赋予缺血耐受性？
• RQ3 药理性预处理在肾移植中是否优于机械性预处理？
• RQ4 该通路的保护作用是否可从无脊椎动物翻译至人类生理？
• RQ5 该靶点是否可发展为一种临床可行的预处理策略，用于如移植等可预测的缺血事件？

主要发现

• 在果蝇中鉴定出一种特定的药理性预处理通路，可增强细胞对缺血再灌注性损伤的耐受性。
• 该通路在哺乳动物模型中的功能具有保守性，表明其具有进化相关性。
• 靶通路的药理激活在肾组织中显著减轻了缺血性损伤。
• 本研究为在临床可预测的环境中实现基于药物的预处理提供了概念验证。
• 目前尚无已知的药物/靶点对在人类临床实践中被验证用于预处理，凸显了该方法的创新性。
• 研究结果表明，靶向该通路可能通过减少再灌注性损伤，改善肾移植的预后。