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: 10507752
• 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/10507752
• 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; Persons; 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.

脓毒症在美国每年影响超过750，000人，并杀死这些患者中的三分之一以上。作为 因此，它已被证明是现代医学的最大挑战之一。的细胞和分子 脓毒症期间组织损伤和器官功能障碍的演变的潜在事件是不活跃的， 研究和承诺，以指导治疗的发展。截至目前，脓毒症的治疗方法是 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。 生物能量学、线粒体和代谢组学是最近的一个热点领域。线粒体反应 现在已知，它们协调下游细胞信号传导反应和结果，从而极大地影响 器官功能和结果。其他人和我们证明，在脓毒症的情况下， 线粒体呼吸和来自线粒体的信号传导来调节炎症 这些反应不仅在脓毒症的早期反应中是重要的，而且对细胞的恢复也是关键的。 我们的初步数据表明，败血症患者有一个受损的线粒体的配置文件。而且那个 衰老与线粒体储备减少和较少的动态响应有关。线粒体健康 以及对刺激的适应能力对于生物体在压力下的生存至关重要。我们发现，在 线粒体呼吸的这种反应被改变，而线粒体通过以下方式协调这种反应： 启动自适应信令响应。因此，线粒体可能变得功能失调，并进行处理， 减轻这一点，包括通过自噬细胞信号传导去除受损的线粒体（控制去除线粒体）。 器官）导致细胞损伤减少。此外，通过以下途径重建健康的线粒体群体： 线粒体的生物合成是确保生存所必需的。 基于此，我们假设如下：线粒体网络的基线"健康"， 通过强大线粒体动态反应进行适应的能力对于限制炎症是至关重要的， 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， 脓毒症的结果。 具体目标2。为了研究如何利用线粒体自噬/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中的器官损伤和线粒体信号传导的作用。这些 新的研究将增加对脓毒症中器官功能障碍的了解，有希望确定在脓毒症中， 风险患者和个性化的脓毒症治疗方法，并将有助于指导发展， 治疗学

项目成果

Circulating Metabolomic Analysis following Cecal Ligation and Puncture in Young and Aged Mice Reveals Age-Associated Temporal Shifts in Nicotinamide and Histidine/Histamine Metabolic Pathways.

• DOI: 10.1155/2021/5534241
• 发表时间: 2021
• 期刊: Oxidative medicine and cellular longevity
• 作者: Cyr A;Kohut L;Chambers L;Stratimirovic S;Zuckerbraun B
• 通讯作者: Zuckerbraun B