Harnessing Fasting Metabolism to Improve Survival in Bacterial Sepsis

利用禁食代谢来提高细菌性脓毒症的存活率

• 批准号: 10027638
• 负责人: sarah huen
• 金额: $ 40.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027638
• 关键词: Acute; Anorexia; Brain; Cellular Stress; Complex; Critical Illness; Data; Endocrine; Fasting; Fibroblast Growth Factor; Genetic; Glucose; Goals; Heart; Hormones; Inflammation; Innate Immune System; Ketones; Kidney; Knockout Mice; Laboratories; Lipids; Lipopolysaccharides; Liver; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methods; Nonesterified Fatty Acids; Nutritional; Nutritional Support; Organ; PPAR alpha; Pathologic; Patients; Pharmacology; Physiology; Production; Sepsis; Starvation; Supplementation; Tissue Model; Tissues; base; body system; fibroblast growth factor 21; improved; insight; ketogenesis; mortality; mouse model; pathogen; response; septic patients

PROJECT SUMMARY Anorexia of acute illness has traditionally been considered a maladaptive response in the face of a presumed hyper-catabolic state. Surprisingly, we found that anorexia is protective in bacterial sepsis. Glucose supplementation during the period of anorexia induced by bacterial sepsis is detrimental and promotes mortality, even in the absence of live pathogen as in the mouse model of lipopolysaccharide (LPS) sepsis. Core fasting metabolic pathways activated in LPS sepsis, including liberation of free fatty acids, ketogenesis, and production of fibroblast growth factor-21 (FGF21), an endocrine FGF hormone that mediates adaptive responses to metabolic stresses such as starvation, are suppressed by glucose supplementation. Knockout mice that are deficient in FGF21 or in peroxisome proliferator-activated receptor alpha, which cannot produce FGF21 or ketones, are more susceptible to bacterial sepsis. We have also found that similar to normal fasting responses, lipid droplets accumulate in the liver and kidney during bacterial sepsis. Emerging evidence suggests that lipid droplets may in fact reflect protective mechanisms against cellular stress rather than lipotoxicity. Based on our preliminary data, we hypothesize that components of fasting metabolism are integral protective mechanisms that support survival and tissue protection during bacterial sepsis. Over the next five years, key goals for the Huen laboratory are to determine whether and how components of fasting metabolism: 1) FGF21, 2) ketogenesis, and 3) lipid droplet formation, are protective in bacterial sepsis. Proposed studies include using pharmacologic targeting and genetic mouse models of tissue-specific deletion of key components of these metabolic processes. Interdisciplinary methods will be used to investigate the interactive physiology between the innate immune system and metabolic organs, in order to elucidate the complex interactions between multiple organ systems including the brain, liver, kidney and heart as part of the adaptive response to bacterial sepsis. The overarching objectives of our proposed studies aim to differentiate between pathologic and protective metabolic pathways in bacterial sepsis, interrogate the beneficial aspects of fasting metabolism that support survival, and elucidate the mechanisms of action.

项目摘要 传统上，急性疾病的厌食症被认为是不良适应的反应 超代谢状态。令人惊讶的是，我们发现厌食症在细菌败血症中具有保护性。葡萄糖 在细菌败血症引起的厌食时期的补充是有害的，并促进死亡率， 即使在没有活病原体的情况下，就像脂多糖（LPS）败血症的小鼠模型中一样。核心禁食 在LPS败血症中激活的代谢途径，包括释放游离脂肪酸，生酮发生和生产 成纤维细胞生长因子21（FGF21），一种内分泌FGF激素，介导对适应性反应的反应 补充葡萄糖抑制诸如饥饿之类的代谢应激。敲除老鼠 缺乏FGF21或过氧化物酶体增殖物激活的受体α，无法产生FGF21或 酮，更容易受到细菌败血症的影响。我们还发现，类似于正常禁食反应， 细菌败血症期间，脂质液滴积聚在肝脏和肾脏中。新兴证据表明脂质 实际上，液滴可能反映了针对细胞应激而不是脂肪毒性的保护机制。基于我们 初步数据，我们假设禁食代谢的组成部分是不可或缺的保护机制 支持细菌败血症期间的生存和组织保护。在接下来的五年中，Huen的主要目标 实验室要确定禁食代谢的组成部分以及如何：1）FGF21，2）生酮发生和 3）脂质液滴形成，在细菌败血症中具有保护性。拟议的研究包括使用药理学 这些代谢过程的关键组成部分的组织特异性缺失的靶向和遗传小鼠模型。 跨学科方法将用于研究先天免疫之间的互动生理 系统和代谢器官，以阐明多个器官系统之间的复杂相互作用 包括大脑，肝脏，肾脏和心脏，作为对细菌败血症的自适应反应的一部分。总体 我们提出的研究的目标旨在区分病理学和保护性代谢途径 细菌败血症，询问支持生存的禁食代谢的有益方面，并阐明 作用机理。