The Mitochondria As Regulators Of Inflammation In Sepsis

线粒体作为脓毒症炎症的调节剂

• 批准号: 10046285
• 负责人: Brian Scott Zuckerbraun
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046285
• 关键词: Address; Affect; Aging; Antibiotics; Area; Autophagocytosis; Behavior; Bioenergetics; Biogenesis; Biology; Caloric Restriction; Categories; Cause of Death; Cell Death; Cells; Cellular biology; Cessation of life; Complex; Critical Care; Data; Development; Disease; Electron Transport; Energy-Generating Resources; Ensure; Environmental Risk Factor; Epigenetic Process; Event; Evolution; Excision; Failure; Family; Functional disorder; Future; Genetic; Health; Human; Infection; Inflammation; Inflammatory Response; Injury; Investigation; Laboratories; Lead; Life Style; Longevity; Maintenance; Measures; Mediating; Mitochondria; Modern Medicine; Molecular; Multiple Organ Failure; Organ; Organism; Outcome; Patient risk; Patients; Pattern; Physical Exercise; Physiology; Population; Process; Publishing; Recovery; Regimen; Regulation; Research; Respiration; Rewards; Risk; Role; Secondary to; Sepsis; Signal Transduction; Stimulus; Stress; Supportive care; Survivors; Syndrome; Testing; Therapeutic; Tissues; United States; Veterans; Work; base; cell injury; clinically relevant; improved outcome; individualized medicine; injured; innovation; insight; lifestyle factors; metabolomics; military veteran; novel; organ growth; organ injury; pathogen; personalized approach; personalized medicine; prevent; reconstitution; response; septic; septic patients; systemic inflammatory response; targeted treatment; therapeutic development; tissue injury

Sepsis affects over 750,000 people per year in the United States and kills over a third of these patients. As such, it has proved to be one of the greatest challenges to modern medicine. The cellular and molecular events underlying the evolution of tissue injury and organ dysfunction during sepsis are under active investigation and promise to guide the development of therapeutics. As of now the treatment of sepsis is limited to treatment of the underlying infection and supportive care, without much of a individualized approach. An area of intense recent focus is bioenergetics, the mitochondria, and metabolomics. Mitochondrial responses are now known to orchestrate downstream cell signaling responses and outcomes, and thus greatly influence organ function and outcomes. Others and we demonstrate that in the setting of sepsis, signals to the mitochondria to regulate mitochondrial respiration and signaling from the mitochondria to regulate inflammatory responses are not only important in the early response to sepsis, but also critical to the recovery of the cell. Our preliminary data show that sepsis patients have a profile of injured mitochondria. Additionally, that aging is associated with decreased mitochondrial reserve and less dynamic responses. Mitochondrial health and the ability to adapt to stimuli are crucial to the survival of organisms during stress. We show that during this response mitochondrial respiration is altered and that the mitochondrion orchestrates this response by initiating adaptive signaling responses. As a result mitochondria may become dysfunctional, and processes to mitigate this, including removal of damaged mitochondria by autophagic cell signaling (controlled removal of the organs) leads to decreased cell injury. Additionally reconstitution of a healthy mitochondrial population via mitochondrial biogenesis is necessary to ensure survival. Based upon this we hypothesize the following: The baseline `health' of the mitochondrial network and the ability to adapt through robust mitochondrial dynamic responses are critical to limit inflammation, tissue injury, and organ dysfunction in sepsis. We will test this hypothesis by addressing the following specific aims: Specific Aim 1. To determine how bioenergetics/mitochondrial health influences organ injury and outcomes in sepsis. Specific Aim 2. To examine how mitophagy/biogenesis inducing therapies can be harnessed for therapeutic benefit in sepsis. Our laboratory has been investigating organ injury in sepsis and the role of mitochondrial signaling. These novel studies will add insight into organ dysfunction in sepsis, have the promise of allowing determination of at risk patients and a personalized approach to sepsis treatment, and will help guide the development of therapeutics.

在美国，败血症每年影响超过75万人，其中超过三分之一的患者死亡。AS 事实证明，这是现代医学面临的最大挑战之一。细胞和分子 脓毒症期间组织损伤和器官功能障碍演变的潜在事件处于活跃状态 调查并承诺指导治疗学的发展。到目前为止，败血症的治疗是 仅限于潜在感染的治疗和支持性护理，没有太多的个性化方法。 最近一个集中关注的领域是生物能量学、线粒体和代谢组学。线粒体反应 现在已知可以协调下游细胞信号反应和结果，从而极大地影响 器官功能和结局。其他的，我们证明在脓毒症的环境中，信号到 线粒体调节线粒体呼吸，线粒体发出信号调节炎症反应 反应不仅在脓毒症的早期反应中很重要，而且对细胞的恢复也很关键。 我们的初步数据显示，脓毒症患者有受损的线粒体。另外，就是 衰老与线粒体储备减少和动态反应减弱有关。线粒体健康 而适应刺激的能力对于有机体在应激状态下的生存至关重要。我们展示了这一点 这一反应改变了线粒体的呼吸作用，线粒体通过 启动自适应信令响应。因此，线粒体可能会变得功能失调，并处理 缓解这种情况，包括通过自噬细胞信号移除受损的线粒体(受控移除 器官)导致细胞损伤减少。此外，通过以下方式重建健康的线粒体种群 线粒体的生物发生是确保生存所必需的。 在此基础上，我们假设如下：线粒体网络和 通过强大的线粒体动态反应进行适应的能力对于限制炎症至关重要， 脓毒症的组织损伤和器官功能障碍。 我们将通过解决以下具体目标来检验这一假设： 具体目标1.确定生物能量学/线粒体健康如何影响器官损伤和 败血症的转归。 具体目标2.研究如何利用有丝分裂/生物发生诱导疗法 脓毒症的治疗益处。 我们的实验室一直在研究脓毒症的器官损伤和线粒体信号的作用。这些 新的研究将增加对脓毒症器官功能障碍的洞察，有望确定AT 风险患者和个性化的脓毒症治疗方法，将有助于指导 治疗学。