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：
Jeffrey Adam Haspel
金额：
$ 19.98万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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

来源：
https://reporter.nih.gov/project-details/8353262
关键词：
Admission activity Affect Animals Basic Science Biological Assay Catabolic Process Cause of Death Cell Death Cell physiology Cells Cessation of life Circadian Rhythms Clinical Cytoplasm Data Disease Functional disorder Health Housekeeping Human Immunology Infection Inflammation Injury Intervention Lead Life Ligation Link Lysosomes Measures Medical Mitochondria Modeling Molecular Morbidity - disease rate Mus Organ Organ failure Organelles Outcome Pathogenesis Pathway interactions Patients Physiological Physiology Proteins Public Health Puncture procedure Recycling Regulation Risk Role Sepsis Severities Shock Starvation Structure Therapeutic Time Training Translational Research United States base circadian pacemaker design experience functional disability human disease improved in vivo mouse model novel novel therapeutics protein aggregate reconstitution septic tool

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）：败血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。它是美国第十大死因，也是一项重大的健康挑战。通过现代医疗管理，大多数患者在脓毒症初期都能存活下来。不幸的是，尽管有目前的治疗方法，许多人仍会出现器官衰竭，其程度决定了他们的死亡风险，以及如果他们存活下来则长期功能受损的风险。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的蛋白质和细胞器累积损伤，破坏其功能并促进细胞死亡。我们假设细胞在脓毒症期间积累受损成分的部分原因是一种称为“巨自噬”的关键管家途径受到抑制，并且这种抑制与脓毒症期间昼夜节律的丧失有关。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，我们建议研究脓毒症小鼠模型以及人类疾病中巨自噬的调节和生理功能。具体而言，我们项目的目标是：1）检查巨自噬在脓毒症小鼠盲肠结扎穿刺（CLP）模型中的调节和意义。 2) 确定实验性脓毒症期间巨自噬破坏和生物钟破坏之间的分子联系。 3) 研究巨自噬在人类脓毒症中的调节。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原因。它将阐明 boh 实验动物和患者败血症期间巨自噬抑制的意义。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，从而减轻脓毒症患者的器官衰竭并改善临床结果。公共卫生相关性：拟议的项目将提高我们对脓毒症的了解，脓毒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性机制在脓毒症期间如何受到影响，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满足重要的公共卫生需求，因为它将用于通过刺激巨自噬来开发治疗脓毒症的新方法，从而限制器官损伤并提高生存率。