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: 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
• 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

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）：败血症是由感染引起的一种威胁生命的疾病，导致系统性炎症，冲击和器官衰竭。它构成了美国的第十个主要死亡原因，代表了主要的健康挑战。在现代医疗管理的情况下，大多数患者在败血症的初始发作中幸存下来。不幸的是，尽管当前的疗法，许多人仍继续发展器官衰竭，其确定其死亡风险的程度，以及如果生存生存的延长功能障碍的风险。作为 这很明显需要更好地限制败血症患者器官衰竭的策略。败血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会累积对其蛋白质和细胞器的损害，破坏其功能并促进细胞死亡。我们假设细胞在败血症过程中积累受损成分的部分原因是因为一种称为“巨噬细胞”的关键家政途径受到抑制，并且这种抑制作用与脓毒症期间的昼夜节律损失有关细胞器。为了研究我们的假设，我们建议研究败血症和人类疾病的小鼠模型中大型噬菌体的调节和生理功能。具体而言，我们项目的目的是：1）检查脓毒症小鼠盲肠结扎和穿刺（CLP）模型的大噬菌学的调节和意义。 2）确定实验性败血症期间大自源破坏与昼夜节律破坏之间的分子联系。 3）检查人类败血症中大自藻的调节。该项目将有助于更好地了解败血症期间器官衰竭，这是导致这种疾病发病率的主要贡献者。它将阐明在BOH实验动物和患者中，败血症期间大噬菌抑制的重要性。这些信息可能会为基于大自藻的干预措施的合理设计提供了减轻败血症患者器官衰竭并改善临床结果的理性设计。 公共卫生相关性：拟议的项目将提高我们对败血症的理解，这是美国的主要健康问题。它将定义一种自适应机制在化粪池疾病期间如何影响称为大自源的机制，以及它如何促进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，因为它将通过刺激大型噬菌学来开发新的治疗败血症的方法，从而限制器官损害和改善生存。