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

基本信息

批准号：
9901685
负责人：
BASILIA ZINGARELLI
金额：
$ 33.39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/9901685
关键词：
5&apos -AMP-activated protein kinase Activities of Daily Living Acute Adult Affect Age Aging Attenuated Autophagocytosis Bioenergetics Biogenesis Biological Biological Models Cardiovascular system Cell Nucleus Cells Clinical Critical Care Critical Illness Cyclic AMP-Dependent Protein Kinases Cytosol Data Defect Disease FRAP1 gene Failure Female Functional disorder Funding Genetic Genetic study Goals Hemorrhage Hemorrhagic Shock Homeostasis Immunity Infection Inflammation Inflammatory Response Injury Intensive Care Units Intervention Investigation Kinetics Laboratories Longevity Maintenance Measurement Metabolic Metabolic Pathway Metabolism Metformin Mitochondria Molecular Molecular Mechanisms of Action Molecular Profiling Morbidity - disease rate Multiple Organ Failure Mus Open Reading Frames Organ Organelles Outcome Pathway interactions Patients Peptides Performance Peroxisome Proliferator-Activated Receptors Pharmacology Pharmacology Study Physiological Physiology Plasma Play Population Process Production Property Protein Kinase Quality Control Recovery Regulation Research Support Respiration Rodent Role Severities Signal Pathway Signal Transduction Signaling Molecule Stat3 protein Stress Testing Therapeutic Tissues Trauma Trauma patient Work age related analog biological adaptation to stress clinically relevant hemodynamics high risk humanin improved in vivo in vivo Model innovation loss of function lung injury male middle age mitochondrial genome mortality mouse model multidisciplinary new therapeutic target novel peptide analog sensor sex small molecule spatiotemporal transcription factor

项目摘要

Project Summary 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.

项目概要创伤引起的多器官功能障碍综合征（MODS）是导致死亡的主要原因重症监护病房。上一个资助周期支持的研究揭示了基本机制通过激活 AMP 激活的 AMP 来调节 MODS 期间的炎症和代谢恢复蛋白激酶 (AMPK)，细胞能量稳态和线粒体质量控制的中央调节器。这目前，工作已顺理成章地进展到研究由 humanin 发起的分子机制，Humanin 是一种线粒体衍生肽在衰老过程中具有假定的细胞保护特性。通过使用临床相关在失血性休克的小鼠模型中，我们观察到血浆护脑素水平的变化与成熟和老年小鼠的 AMPK 衰竭和器官损伤的严重程度，但年轻小鼠则不然。此外，管理有效的护脑素类似物护脑素-G (HNG) 和 colivelin，在 AMPK- 依赖和独立的方式，还涉及信号转导器和转录激活器3 （统计3）。本提案旨在了解护脑素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通过采用丢失的遗传和药理学方法来剖析这些串扰的研究 AMPK 和 STAT3 的功能，以及在体内综合生理学模型系统中使用护脑素类似物结合分子概况和功能测量。将特别考虑生物学因素已知影响危重患者器官损伤进展和结果的年龄和性别变量。具体来说，我们将确定：1）失血性休克期间护脑素的时空动力学与 MODS 相关； 2)护脑素在调节MODS的病理生理学方面具有生物学作用； 3)护脑素有助于通过 AMPK 独立代谢途径或 AMPK- 调节线粒体功能通过调节 STAT3 亚细胞定位和激活的独立信号传导。成功者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和确定可以对临床干预产生重大影响的新治疗靶点。