AGE-DEPENDENT MECHANISMS OF METABOLIC RECOVERY IN HEMORRHAGIC SHOCK

项目摘要（受资助的母基金/项目） 多器官功能障碍综合征（MODS），继发于创伤，是一个主要的潜在原因，死亡率， 重症监护室上一个供资周期支持的研究揭示了基本机制 在MODS期间通过激活AMP激活的 蛋白激酶（AMPK），细胞能量稳态和线粒体质量控制的中心调节剂。这 现在的工作已经合乎逻辑地发展到研究由人蛋白启动的分子机制， 线粒体衍生肽在衰老过程中具有假定的细胞保护特性。通过使用临床相关的 在失血性休克的小鼠模型中，我们观察到血浆人素水平的变化与 AMPK衰竭和器官损伤的严重程度在成熟和老年小鼠，但不是年轻的小鼠。此外，行政 有效的humanin类似物humanin-G（HNG）和colivelin在AMPK-1中提供了有益的效果。 依赖性和非依赖性方式，还涉及信号转导和转录激活因子3 （STAT3）。目前的建议旨在了解humanin如何参与这些信号通路， 改善线粒体功能，促进器官代谢恢复。我们将进行多学科的 研究通过采用遗传学和药理学方法来分析这些串扰， AMPK和STAT 3的功能，并通过在体内整合生理学的模型系统中使用人蛋白类似物 结合分子图谱和功能测量。将特别考虑生物 已知影响危重患者器官损伤进展和结局的年龄和性别变量。 具体来说，我们将确定：1）在失血性休克过程中， 与MODS相关; 2）humanin在调节MODS的病理生理学中具有生物学作用; 3）humanin 通过AMPK-非依赖性代谢途径或AMPK-调节线粒体功能。 通过调节STAT 3亚细胞定位和激活的独立信号传导。成功 这项工作的完成将揭示线粒体质量控制的基本应激反应回路， 确定可能对临床干预产生重大影响的新治疗靶点。

Project Summary (of the funded parent award/project) Multiple organ dysfunction syndrome (MODS), consequent to trauma, is a major underlying cause of mortality in intensive care units. Research supported by the previous funding cycle has revealed fundamental mechanisms that modulate inflammation and metabolic recovery during MODS through activation of the AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis and mitochondrial quality control. This work has now logically progressed to investigating the molecular machinery that is initiated by humanin, a mitochondrial derived peptide with putative cytoprotective properties in aging. By using a clinically relevant murine model of hemorrhagic shock, we have observed that changes in plasma humanin levels correlate with AMPK failure and severity of organ injury in mature and old, but not young mice. Furthermore, administration of the potent humanin analogues, humanin-G (HNG) and colivelin, afforded beneficial effects in an AMPK- dependent and -independent manner, also involving the signal transducer and activator of transcription 3 (STAT3). The present proposal seeks to understand how humanin participates in these signaling pathways to improve mitochondrial function and promote organ metabolic recovery. We will conduct a multidisciplinary investigation to dissect these cross-talks by employing both genetic and pharmacological approaches of loss-of- function of AMPK and STAT3, and by using humanin analogues in model systems of in vivo integrated physiology combining molecular profiles and functional measurements. A special consideration will be given to the biological variables of age and sex that are known to affect progress of organ injury and outcomes in critically ill patients. Specifically, we will determine whether: 1) the spatio-temporal kinetics of humanin during hemorrhagic shock correlate with MODS; 2) humanin has a biological role in modulating the pathophysiology of MODS; 3) humanin contributes to the regulation of mitochondrial function by AMPK-independent metabolic pathways or AMPK- independent signaling through modulation of STAT3 subcellular localization and activation. The successful completion of this work will reveal fundamental stress-responsive circuits of mitochondrial quality control and identify new therapeutic targets that can have a major impact in clinical intervention.