Role of Macroautophagy and Circadian Clock Disruption in Sepsis Pathogenesis

描述(申请人提供)：败血症是一种威胁生命的疾病，由感染引起，导致全身炎症、休克和器官衰竭。它构成了美国第十大主要死因，也是一个重大的健康挑战。有了现代医疗管理，大多数患者在最初的脓毒症发作时都能存活下来。不幸的是，许多人继续发展为器官衰竭，尽管目前的治疗方法，其程度决定了他们的死亡风险，以及他们的长期功能损害的风险，如果他们生存下来。AS 因此，显然需要更好的策略来限制脓毒症患者的器官衰竭。脓毒症导致器官衰竭的原因是，在这种疾病期间，组成重要器官的细胞对其蛋白质和细胞器积累了损害，破坏了它们的功能，并促进了细胞死亡。我们推测，细胞在脓毒症过程中积累受损成分的部分原因是一个关键的内务处理途径被抑制，这种抑制与脓毒症过程中昼夜节律的丧失有关。宏自噬是一种分解代谢过程，细胞通过这种分解过程吞噬细胞质的成分，以便在饥饿条件下生存并回收受损的细胞器。为了验证我们的假设，我们建议在脓毒症小鼠模型中以及在人类疾病中研究巨自噬的调节和生理功能。具体地说，本项目的目的是：1)研究巨噬细胞自噬在小鼠盲肠结扎穿孔(CLP)脓毒症模型中的调节和意义。2)确定实验性脓毒症时巨噬细胞自噬中断与昼夜节律紊乱之间的分子联系。3)研究巨噬细胞自噬在人类败血症中的调节作用。这个项目将有助于更好地了解脓毒症期间的器官衰竭，这是导致这种疾病发病率的主要因素。它将阐明在BOH实验动物和患者的脓毒症过程中抑制巨自噬的意义。这些信息可能有助于合理设计基于宏自噬的干预措施，减轻脓毒症患者的器官衰竭，并导致临床结果的改善。

DESCRIPTION (provided by applicant): Sepsis is a life-threatening disorder caused by infection that leads to systemic inflammation, shock and organ failure. It constitutes the tenth leading cause of death in the United States and represents a major health challenge. With modern medical management most patients survive the initial onset of sepsis. Unfortunately, many go on to develop organ failure despite current therapies, the extent of which determines their risk of death, and also their risk of prolonged functional impairment should they survive. As such, there is a clear need for better strategies to limit organ failure in sepsis patients. The reason sepsis leads to organ failure is because, during this disease, the cells that make up vital organs accumulate damage to their proteins and organelles, undermining their function and also promoting cell death. We hypothesize that part of the reason that cells accumulate damaged components during sepsis is because a key housekeeping pathway called "macroautophagy" becomes inhibited, and that this inhibition is related to a loss of circadian rhythms during sepsis Macroautophagy is a catabolic process by which cells cannibalize components of their cytoplasm in order to survive starvation conditions and to recycle damaged organelles. To investigate our hypothesis, we propose to investigate the regulation and physiologic function of macroautophagy in mouse models of sepsis and also in human disease. Specifically the aims of our project are: 1) To examine the regulation and significance of macroautophagy in the mouse cecal ligation and puncture (CLP) model of sepsis. 2) To determine the molecular link between macroautophagy disruption and circadian clock disruption during experimental sepsis. 3) To examine the regulation of macroautophagy in human sepsis. This project will contribute to a better understanding of organ failure during sepsis, which is a major contributor to the morbidity of this disorder. It will clarify the significance of macroautophagy inhibition during sepsis in boh experimental animals and patients. Such information may inform the rational design of macroautophagy- based interventions that mitigate organ failure in sepsis patients and lead to improved clinical outcomes.