Role of Macroautophagy and Circadian Clock Disruption in Sepsis Pathogenesis

巨自噬和昼夜节律紊乱在脓毒症发病机制中的作用

基本信息

  • 批准号:
    8353262
  • 负责人:
  • 金额:
    $ 19.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

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. PUBLIC HEALTH RELEVANCE: The proposed project will improve our understanding of sepsis, which is a major health issue in the United States. It will define how an adaptive mechanism called macroautophagy is affected during septic illness, and how it contributes to the severity and outcome of this important disease. The information our project produces will serve an important public health need, as it will be used to develop new ways of treating sepsis by stimulating macroautophagy, thereby limiting organ damage and improving survival.
描述(由申请人提供):脓毒症是一种由感染引起的危及生命的疾病,可导致全身炎症、休克和器官衰竭。它是美国第十大死亡原因,是一个重大的健康挑战。随着现代医疗管理,大多数患者在败血症的初始发作中存活。不幸的是,尽管有目前的治疗,许多人继续发展器官衰竭,其程度决定了他们的死亡风险,以及如果他们存活,他们长期功能障碍的风险。作为 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,构成重要器官的细胞积累对其蛋白质和细胞器的损害,破坏其功能并促进细胞死亡。我们推测,脓毒症期间细胞积累受损成分的部分原因是因为一种称为“大自噬”的关键管家途径受到抑制,这种抑制与脓毒症期间昼夜节律的丧失有关。大自噬是一种分解代谢过程,细胞通过该过程蚕食其细胞质的成分,以便在饥饿条件下生存并回收受损的细胞器。为了研究我们的假设,我们建议在败血症小鼠模型和人类疾病中研究巨自噬的调节和生理功能。本课题的主要目的是:1)探讨脓毒症小鼠盲肠结扎穿孔(CLP)模型中巨细胞自噬的调控及其意义。2)确定实验性脓毒症中大细胞自噬破坏和生物钟破坏之间的分子联系。3)探讨脓毒症中巨细胞自噬的调控。该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的主要因素。这将有助于阐明大自噬抑制在实验动物和患者脓毒症中的意义。这些信息可以为基于巨自噬的干预措施的合理设计提供信息,这些干预措施可以减轻脓毒症患者的器官衰竭并改善临床结局。 公共卫生相关性:拟议的项目将提高我们对败血症的理解,败血症是美国的一个主要健康问题。它将定义一种称为巨自噬的适应机制在脓毒性疾病中如何受到影响,以及它如何影响这种重要疾病的严重程度和结果。我们的项目产生的信息将服务于一个重要的公共卫生需求,因为它将被用来开发新的方法来治疗败血症通过刺激巨自噬,从而限制器官损伤和提高生存率。

项目成果

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Jeffrey Adam Haspel其他文献

Jeffrey Adam Haspel的其他文献

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{{ truncateString('Jeffrey Adam Haspel', 18)}}的其他基金

Circadian Signatures in Chronic Lung Disease
慢性肺病的昼夜节律特征
  • 批准号:
    10410498
  • 财政年份:
    2020
  • 资助金额:
    $ 19.98万
  • 项目类别:
Circadian Signatures in Chronic Lung Disease
慢性肺病的昼夜节律特征
  • 批准号:
    10221776
  • 财政年份:
    2020
  • 资助金额:
    $ 19.98万
  • 项目类别:
Circadian Signatures in Chronic Lung Disease
慢性肺病的昼夜节律特征
  • 批准号:
    10665013
  • 财政年份:
    2020
  • 资助金额:
    $ 19.98万
  • 项目类别:
Circadian Signatures in Chronic Lung Disease
慢性肺病的昼夜节律特征
  • 批准号:
    10025551
  • 财政年份:
    2020
  • 资助金额:
    $ 19.98万
  • 项目类别:
Clock Gene Control of Viral Infection and Asthma
病毒感染和哮喘的时钟基因控制
  • 批准号:
    9213858
  • 财政年份:
    2016
  • 资助金额:
    $ 19.98万
  • 项目类别:
Clock Gene Control of Viral Infection and Asthma
病毒感染和哮喘的时钟基因控制
  • 批准号:
    10064005
  • 财政年份:
    2016
  • 资助金额:
    $ 19.98万
  • 项目类别:
Clock Gene Control of Viral Infection and Asthma
病毒感染和哮喘的时钟基因控制
  • 批准号:
    9402650
  • 财政年份:
    2016
  • 资助金额:
    $ 19.98万
  • 项目类别:
Role of Macroautophagy and Circadian Clock Disruption in Sepsis Pathogenesis
巨自噬和昼夜节律紊乱在脓毒症发病机制中的作用
  • 批准号:
    8913997
  • 财政年份:
    2012
  • 资助金额:
    $ 19.98万
  • 项目类别:
Role of Macroautophagy and Circadian Clock Disruption in Sepsis Pathogenesis
巨自噬和昼夜节律紊乱在脓毒症发病机制中的作用
  • 批准号:
    8538470
  • 财政年份:
    2012
  • 资助金额:
    $ 19.98万
  • 项目类别:
Role of Macroautophagy and Circadian Clock Disruption in Sepsis Pathogenesis
巨自噬和昼夜节律紊乱在脓毒症发病机制中的作用
  • 批准号:
    8721440
  • 财政年份:
    2012
  • 资助金额:
    $ 19.98万
  • 项目类别:

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