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

自噬通过溶酶体降解和受损/功能失调的细胞器（如线粒体）的再循环，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稳态。人们已经认识到自噬与炎症之间存在反比关系，如自噬下降，炎症增加。衰老影响自噬和炎症，使自噬下降，形成慢性炎症状态。有人认为，慢性炎症增加了对与年龄有关的疾病/残疾的易感性。代谢综合征（MetS）是一组危险因素，确定了患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，并伴随着炎症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，已知可诱导进一步炎症并与代谢综合征相关。最近的研究表明，自噬与诱导IL-1B和IL-18产生的NLRP3炎性体和nf - K - B通路之间存在联系[为了本提议的目的，这被称为自噬/有丝自噬-IL-1B/18通路]。本应用的总体目标是验证心脏缺血/再灌注（l/R）模型中自噬和炎症相互依赖的假设，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。来检验假设。我们将使用实验控制其自噬活性的小鼠（目的1），自然减少自噬的老年小鼠（目的2），以及表现出炎症水平升高的met啮齿动物/猪（目的3）。具体:

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.