Age-related changes in autophagy and reffects on inflammation and the heart

年龄相关的自噬变化以及对炎症和心脏的影响

• 批准号: 8923333
• 负责人: linton phyllis-Jean
• 金额: $ 44.18万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8923333
• 关键词: Affect; Age; Aging; Animals; Autophagocytosis; Binding; Cardiac; Cardiovascular Diseases; Cells; Chronic; Comorbidity; Coupled; Cytosol; Data; Diet; Disease; Dissociation; Excision; Exhibits; Exposure to; Family suidae; Fatty acid glycerol esters; Genetic; Goals; Health; Heart; Homeostasis; Infarction; Inflammation; Inflammatory; Injury; Instruction; Interleukin-1; Interleukin-10; Interleukin-18; Knock-out; Laboratories; Lead; Link; Lipopolysaccharides; Metabolic syndrome; Methods; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Outcome; Oxidative Stress; Pathology; Pathway interactions; Population; Predisposition; Production; Proteins; Reaction; Reactive Oxygen Species; Recycling; Reperfusion Therapy; Respiratory Burst; Risk; Risk Factors; Rodent; Role; Severities; Signal Transduction; Starvation; Stress; Testing; Thioredoxin; Time; Tissues; Work; age effect; age related; aged; chemokine; coronary artery occlusion; cytokine; disability; driving force; improved; macrophage; mutant; neutrophil; protein aggregate; receptor; response; stressor

Autophagy maintains cellular homeostasis by lysosomal degradation and recycling of damaged/dysfunctional organelles (such as mitochondna), removal of aggregated proteins, and the provision of energy to cells in times of stress. It has been recognized that an inverse relationship between autophagy and inflammation exists, such that as autophagy declines, inflammation increases. Aging affects autophagy and inflammation such that autophagy declines and a chronic inflammatory state develops. It has been argued that chronic inflammation enhances the susceptibility to age-related diseases/disabilities. Metabolic syndrome (MetS) is a cluster of risk factors that identifies a population with increased risk of developing type II diabetes and cardiovascular disease. This condition is brought on by high-fat diets, is prevalent in the aged and is coupled with elevated basal levels of inflammatory cytokines. IL-1B and IL-18 are early, pro-inflammatory cytokines that are known to induce further inflammation and are associated with metabolic syndrome. Recent work demonstrates a link between autophagy and the NLRP3 inflammasome and N F - K B pathways that induce IL-1B and IL-18 production [For the purpose of this proposal, this is called autophagy/mitophagy-to-IL-1B/18 pathway.]. The overall goal of this application is to test the hypothesis that autophagy and inflammation in the cardiac ischemia/reperfusion (l/R) model are interdependent and modulation of autophagy will affect levels of inflammation and hence the severity of cardiac injury post l/R. To test the hypothesis. we will use mice that have their autophagic activity experimentally manipulated (Aim 1), aged mice that naturally have diminished autophagy (Aim 2), and rodents/swine with MetS that exhibit elevated levels of inflammation (Aim 3). Specifically: ¿ Aim 1 will assess the effect of modulating autophagy on inflammation and cardiac injury after permanent coronary artery occlusion and the role of the mitophagy-to-IL-1B/18 pathway in infarct size and remodeling; Aim 2 will assess the effect of age on autophagy and inflammation in cardiac l/R; Aim 3 will assess the effect of MetS on autophagy and inflammation in cardiac l/R. These studies will identify step(s) in the autophagy/mitophagy-to-IL-1B/18 pathway that can be modulated to reduce inflammation, preserve autophagy and thus, ameliorate injury post l/R.

自噬通过溶酶体降解和受损/功能失调的细胞器（如线粒体DNA）的再循环、去除聚集的蛋白质以及在应激时向细胞提供能量来维持细胞稳态。已经认识到，自噬和炎症之间存在反比关系，使得随着自噬下降，炎症增加。衰老影响自噬和炎症，使得自噬下降并发展成慢性炎症状态。有人认为，慢性炎症增加了对年龄相关疾病/残疾的易感性。代谢综合征（MetS）是一组危险因素，可确定患有II型糖尿病和心血管疾病风险增加的人群。这种情况是由高脂肪饮食引起的，在老年人中普遍存在，并伴有炎症细胞因子的基础水平升高。IL-1B和IL-18是早期促炎细胞因子，已知其可诱导进一步炎症并与代谢综合征相关。最近的工作证明了自噬与诱导IL-1 B和IL-18产生的NLRP 3炎性体和NF-κ B B途径之间的联系[出于本建议的目的，这被称为自噬/线粒体自噬至IL-1 B/18途径]。本申请的总体目标是测试心脏缺血/再灌注（I/R）模型中的自噬和炎症是相互依赖的并且自噬的调节将影响炎症水平并因此影响I/R后心脏损伤的严重性的假设。为了检验这个假设。我们将使用具有实验操纵的自噬活性的小鼠（目标1）、自然具有减弱的自噬的老年小鼠（目标2）和具有表现出升高的炎症水平的MetS的啮齿动物/猪（目标3）。具体而言： 目标1将评估调节自噬对永久性冠状动脉闭塞后炎症和心脏损伤的影响，以及线粒体自噬至IL-1B/18通路在梗死面积和重塑中的作用; 目的2：探讨年龄对心肌缺血再灌注损伤中自噬和炎症的影响; 目的3将评估MetS对心脏I/R中的自噬和炎症的影响。 这些研究将确定自噬/线粒体自噬至IL-1B/18通路中的步骤，这些步骤可以被调节以减少炎症，保护自噬，从而改善I/R后的损伤。