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

自噬通过溶酶体的降解和受损/功能障碍的细胞器(如有丝分裂)的循环，去除聚集的蛋白质，以及在应激时为细胞提供能量来维持细胞的动态平衡。人们已经认识到，自噬和炎症之间存在着相反的关系，当自噬减弱时，炎症就会增加。衰老影响自噬和炎症，导致自噬减弱，形成慢性炎症状态。有人认为，慢性炎症增加了与年龄相关的疾病/残疾的易感性。代谢综合征(METS)是一组危险因素，用于识别罹患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，在老年人中很普遍，并伴随着炎性细胞因子基础水平的升高。IL-1B和IL-18是早期的促炎细胞因子，已知可引起进一步的炎症，并与代谢综合征有关。最近的工作证明了自噬与NLRP3炎症体和诱导IL-1B和IL-18产生的N F-K B通路之间的联系[在本提案中，这被称为自噬/有丝分裂噬到IL-1B/18的通路。]。本应用的总体目标是验证这样一种假设，即在心脏缺血/再灌注(L/R)模型中，自噬和炎症是相互依赖的，自噬的调节将影响炎症水平，从而影响L/R后心脏损伤的严重程度。我们将使用具有实验操作的自噬活动的小鼠(目标1)，自然减少自噬的老龄小鼠(目标2)，以及表现出炎症水平升高的甲硫氨酸的啮齿动物/猪(目标3)。具体地说，就是： 目的1评价自噬调节在冠状动脉永久性闭塞后炎症和心脏损伤中的作用，以及有丝分裂吞噬到IL-1B/18通路在梗塞面积和重构中的作用； 目的2研究AGE对L/R心肌细胞自噬和炎症反应的影响； 目的3评价蛋氨酸对L/R心肌细胞自噬和炎症的影响。 这些研究将确定自噬/有丝分裂吞噬到IL-1B/18通路中的步骤(S)，该步骤可以被调节以减少炎症，保护自噬，从而减轻L/R后的损伤。

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.