AGE-DEPENDENT MECHANISMS OF METABOLIC RECOVERY IN HEMORRHAGIC SHOCK

失血性休克代谢恢复的年龄依赖性机制

• 批准号: 10388734
• 负责人: BASILIA ZINGARELLI
• 金额: $ 12.06万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388734
• 关键词: 5' -AMP-activated protein kinase; Adult; Affect; Age; Aging; Award; Biological; Biological Models; Clinical; Critical Care; Critical Illness; Cyclic AMP-Dependent Protein Kinases; Failure; Functional disorder; Funding; Genetic; Genetic study; Hemorrhagic Shock; Homeostasis; Inflammation; Injury; Intensive Care Units; Intervention; Investigation; Kinetics; Maintenance; Measurement; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Molecular Profiling; Morbidity - disease rate; Multiple Organ Failure; Mus; Organ; Outcome; Parents; Patients; Peptides; Pharmacology; Pharmacology Study; Physiology; Plasma; Population; Property; Protein Kinase; Quality Control; Recovery; Regulation; Research Support; Role; Severities; Signal Pathway; Signal Transduction; Stat3 protein; Stress; Trauma; Trauma patient; Work; age related; analog; clinically relevant; high risk; humanin; improved; in vivo; in vivo Model; loss of function; mortality; mouse model; multidisciplinary; new therapeutic target; novel; organ injury; sex; spatiotemporal

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.

项目摘要(受资助的父级奖项/项目) 创伤引起的多器官功能障碍综合征(MODS)是导致 重症监护室。前一个资金周期支持的研究揭示了基本的机制 通过激活AMP激活的AMP调节MODS期间的炎症和代谢恢复 蛋白激酶(AMPK)，细胞能量平衡和线粒体质量控制的中心调节者。这 从逻辑上讲，现在的工作已经取得进展，研究由人类凝集素启动的分子结构 线粒体衍生的多肽，在衰老过程中具有假定的细胞保护特性。通过使用临床上相关的 在失血性休克小鼠模型上，我们观察到血浆人蛋白水平的变化与 AMPK的失效和器官损伤的严重程度在成熟和老年小鼠中，但不是幼年小鼠。此外，管理 有效的人蛋白类似物，人蛋白G(HNG)和Colivelin，在AMPK中提供了有益的效果。 依赖和独立的方式，也涉及信号转导和转录激活因子3 (统计数据3)。目前的建议试图了解人是如何参与这些信号通路的 改善线粒体功能，促进器官代谢恢复。我们将进行一项多学科的 采用遗传学和药理学方法对这些交叉对话进行研究。 AMPK和STAT3的功能及其在体内综合生理学模型系统中的应用 结合分子图谱和功能测量。将特别考虑到生物 已知的影响危重患者器官损伤进展和预后的年龄和性别变量。 具体地说，我们将确定：1)失血性休克期间人蛋白的时空动力学 与MODS相关；2)人蛋白在调节MODS的病理生理过程中起生物学作用；3)人蛋白 通过AMPK非依赖性代谢途径或AMPK- 通过调节STAT3亚细胞定位和激活的独立信号。成功者 这项工作的完成将揭示线粒体质量控制和应激反应的基本电路 确定能够对临床干预产生重大影响的新的治疗靶点。