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: 9128011
• 负责人: BASILIA ZINGARELLI
• 金额: $ 30.81万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128011
• 关键词: 5' -AMP-activated protein kinase; Acute; Adopted; Affect; Age; Aging; Autophagocytosis; Bioenergetics; Biogenesis; Cardiovascular Physiology; Cause of Death; Cell Death; Cells; Clinical; Complex; Critical Care; Data; Deacetylase; Drug usage; Elderly; Event; FRAP1 gene; Functional disorder; Genetic study; Goals; Health; Hemorrhage; Hemorrhagic Shock; Hour; Impairment; Inflammation; Inflammatory Response; Injury; Kidney; Knockout Mice; Lead; Liquid substance; Mediating; Metabolic; Metformin; Mitochondria; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Multiple Organ Failure; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Organ; Organelles; Oxidative Stress; PPAR gamma; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacological Treatment; Phosphotransferases; Play; Population; Process; Property; Protocols documentation; Rattus; Recovery; Regulation; Reperfusion Therapy; Resuscitation; Risk Factors; Rodent Model; Role; STK11 gene; Severities; Signal Pathway; Signaling Molecule; Testing; Therapeutic; Trauma; Trauma patient; age related; anti aging; clinically relevant; functional restoration; gain of function; high risk; improved; infancy; juvenile animal; mitochondrial autophagy; mitochondrial dysfunction; mortality; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; response to injury; senescence; sensor; success; treatment strategy

 DESCRIPTION (provided by applicant): Multiple organ failure (MOF) is a leading cause of death in trauma patients. Even with success of acute trauma management with fluid resuscitation and organ support protocols, many patients who survive their initial trauma are at high risk to progress towards a persistent organ injury. Clinical evidence suggests that advanced age is a risk factor for persistence of MOF and mortality. The molecular mechanisms and the impact of age in the persistence of MOF are yet to be defined. Furthermore, therapeutic strategies to promote recovery of organ function remain unavailable. Scientific evidence suggests that mitochondrial dysfunction is a critical pathogenetic event of MOF. In preliminary studies, we have observed that autophagy, an important process which enables the cells to dispose defective mitochondria, is impaired during hemorrhagic shock in the kidney of old rats (18-24 months) when compared to younger animals (2-3 months). This age-dependent impairment of autophagy correlates with severity of kidney injury and inflammatory response. At molecular analysis, we have identified AMP-activated protein kinase (AMPK) as a key signaling molecule regulating organ function and potential recovery after hemorrhagic shock. This kinase is a crucial energy status sensor, which is known to negatively regulate the autophagy controller the mammalian target of rapamycin complex 1 (mTORC1). Conversely, AMPK activates the peroxisome proliferator-activated receptor (PPAR)¿ coactivator 1-a (PGC-1a), the master regulator of mitochondrial biogenesis, i.e. the process of restoration of functional mitochondria. Of clinical relevance, we have also observed that treatment with metformin, a common drug used for type 2 diabetes that activates AMPK through the upstream liver kinase B1 (LKB1), reduces kidney inflammation and ameliorates cardiovascular function in old rats subjected to hemorrhagic shock. Thus, our preliminary data raise the novel hypothesis that an age-dependent dysregulation of AMPK causes impairment of autophagy and reduction of mitochondrial biogenesis, leading to persistence of organ injury during hemorrhagic shock. The long-term goal of this project is to identify target pathways and to evaluate pharmacological treatments for organ dysfunction by maintaining proper disposal of damaged organelle and promoting organ recovery. Three aims are proposed to validate these novel concepts. In aim 1 we will determine the age-dependent alterations of autophagy and mitochondrial biogenesis and their correlation with AMPK activation during hemorrhagic shock in major organs of rats of different ages. In aim 2 we will adopt pharmacological studies to determine the role of AMPK on hemorrhage-induced systemic inflammatory response, MOF and lethality in rats of different ages. In aim 3 we will use AMPKa knockout mice to define the molecular mechanisms by which AMPK activates autophagy and mitochondrial biogenesis through regulation of mTORC1, PGC-1a, and SIRT1, a deacetylase described for its anti-aging properties. These studies may unveil novel regulatory paradigms that impact organ metabolic recovery and may lead to new therapies in hemorrhagic shock.

 描述（由申请人提供）：多器官衰竭（MOF）是创伤患者死亡的主要原因。即使成功的急性创伤管理与液体复苏和器官支持协议，许多患者谁生存的初始创伤是在高风险的进展，以持续性器官损伤。临床证据表明，高龄是MOF持续存在和死亡的危险因素。MOF持续存在的分子机制和年龄的影响尚未确定。此外，仍然没有促进器官功能恢复的治疗策略。科学证据表明，线粒体功能障碍是MOF的关键发病事件。在初步研究中，我们已经观察到，自噬，一个重要的过程，使细胞处理有缺陷的线粒体，在老年大鼠（18-24个月）的肾脏出血性休克期间受损时，与年轻的动物（2-3个月）。这种年龄依赖性的自噬损伤与肾损伤和炎症反应的严重程度相关。在分子分析中，我们已经确定AMP活化蛋白激酶（AMPK）作为一个关键的信号分子调节器官功能和潜在的恢复失血性休克后。这种激酶是一种重要的能量状态传感器，已知其负调节自噬控制器雷帕霉素复合物1（mTORC 1）的哺乳动物靶标。相反，AMPK激活过氧化物酶体增殖物激活受体（PPAR）辅激活因子1-a（PGC-1a），这是线粒体生物发生的主要调节因子，即功能性线粒体的恢复过程。具有临床意义的是，我们还观察到，二甲双胍（一种用于2型糖尿病的常用药物，通过上游肝激酶B1（LKB 1）激活AMPK）治疗可减少老年大鼠失血性休克时的肾脏炎症并改善心血管功能。因此，我们的初步数据提出了一个新的假设，年龄依赖性的AMPK失调导致自噬损伤和线粒体生物合成减少，导致出血性休克期间器官损伤的持续性。该项目的长期目标是确定靶向途径，并通过维持受损细胞器的适当处置和促进器官恢复来评估器官功能障碍的药物治疗。提出了三个目标来验证这些新的概念。在目的1中，我们将确定自噬和线粒体生物合成的年龄依赖性变化及其与AMPK激活在失血性休克期间的主要器官的不同年龄的大鼠。目的二：通过药理学研究，探讨AMPK对不同年龄大鼠烫伤诱导的全身炎症反应、多器官功能衰竭及致死率的影响。在目标3中，我们将使用AMPKa基因敲除小鼠来定义AMPK通过调节mTORC 1，PGC-1a和SIRT 1（一种因其抗衰老特性而被描述的脱乙酰酶）来激活自噬和线粒体生物合成的分子机制。这些研究可能揭示影响器官代谢恢复的新的调节模式，并可能导致出血性休克的新疗法。