Mechanisms of sepsis-associated muscle stem cell dysfunction

脓毒症相关肌肉干细胞功能障碍的机制

• 批准号: 10187588
• 负责人: Jason Doles
• 金额: $ 39.65万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187588
• 关键词: Acute; Address; Adult; Area; Award; Biochemical Pathway; Biochemistry; Bioinformatics; Biological Markers; Breathing; Cachexia; Cellular Metabolic Process; Cellular biology; Chronic Disease; Clinic; Clinical; Clinical Management; Defect; Environment; Exhibits; Functional disorder; Goals; Impaired cognition; Impairment; Incidence; Intensive Care; Laboratories; Life; Long-Term Effects; Metabolic; Metabolism; Modeling; Molecular Biology; Mus; Muscle; Muscle Weakness; Muscle satellite cell; Muscular Atrophy; National Institute of General Medical Sciences; Natural regeneration; Pathway interactions; Positioning Attribute; Recovery; Reporting; Research; Sepsis; Septic Shock; Signaling Molecule; Skeletal Muscle; Skeletal Muscle Satellite Cells; Survivors; Tissues; Training; Work; cost efficient; cytokine; experience; experimental study; faculty mentor; faculty research; improved; lipid metabolism; metabolomics; mortality; mouse model; programs; public health relevance; repaired; stem cell biology; stem cell differentiation; stem cell function; stem cell population; stem cells; wasting

ABSTRACT Sepsis is a life-threatening condition commonly encountered in intensive care settings. While advancements in clinical sepsis management have lowered acute sepsis mortality rates, a growing number of severe sepsis survivors progress to chronic illness states. Indeed, many survivors report persistent muscle weakness, breathing difficulties, and cognitive decline as debilitating complications in their post-sepsis life. We hypothesize that a key to managing the long-term effect of sepsis is to understand how sepsis-associated circulating factors impact the metabolic state of long-lived, tissue specific stem cells. Given the high incidence of post-sepsis muscle dysfunction, we propose to initially evaluate acute and persistent metabolic defects in skeletal muscle stem cells. In adult skeletal muscle, satellite cells are the primary resident stem cell population and are indispensible contributors to skeletal muscle repair and regeneration. Since establishing my independent laboratory, we have made significant progress towards understanding how wasting-associated factors impair satellite/muscle stem cell (SC) biology and we are well positioned to explore the mechanistic and metabolic basis of muscle dysfunction following septic shock. The big picture question proposed in this MIRA/R35 application is: How do sepsis-associated factors impact SC function? This proposal highlights three of our developing project areas that address this central question using distinct experimental and conceptual tactics. First, we will explore how sepsis-associated cytokines modulate SC metabolism. We found that muscle wasting/cachexia-associated cytokines can augment pathways involved in regulating energetic metabolism and propose to define the effects of sepsis-associated cytokine exposure on lipid metabolism in SCs. Second, we will examine the mechanisms by which sepsis-associated metabolites impact SC function. We present evidence that wasting-associated metabolites can antagonize stem cell differentiation and propose investigating the hypothesis that some of these sepsis metabolic biomarkers also function as bioactive signaling molecules capable of augmenting SC activation. Third, we will leverage cutting edge metabolomics analyses of muscle stem cells isolated from murine sepsis models to define metabolic signatures associated with sepsis onset and extended recovery. We show that SCs can exhibit sustained metabolic alterations to acute metabolic disruptions and propose that sepsis-associated metabolic derangements compromise SC metabolic networks long into the recovery period. These three proposed project areas are supported by rigorous past training in stem cell biology, a vibrant research and clinical environment at the Mayo Clinic, and continued professional support and guidance from experienced faculty mentors. Overall, successful completion of this proposed MIRA/R35 award will: a) facilitate the establishment of a dynamic, independent, and cost- efficient NIGMS-focused junior faculty research program at the Mayo Clinic, b) advance our understanding of how stem cells respond and adapt to sepsis-associated factors, and c) drive the field of long-term sepsis management into new and underexplored areas, such as stem cell manipulation and metabolic reprogramming.

抽象的 脓毒症是重症监护室中常见的危及生命的疾病。尽管 临床脓毒症管理的进步降低了急性脓毒症死亡率，越来越多的人 严重脓毒症幸存者进展为慢性疾病状态。事实上，许多幸存者报告说，肌肉持续存在 虚弱、呼吸困难和认知能力下降是脓毒症后生活中使人衰弱的并发症。我们 假设管理脓毒症长期影响的关键是了解脓毒症如何与脓毒症相关 循环因素影响长寿、组织特异性干细胞的代谢状态。鉴于发病率高 对于脓毒症后肌肉功能障碍，我们建议初步评估急性和持续性代谢缺陷 骨骼肌干细胞。在成人骨骼肌中，卫星细胞是主要的常驻干细胞群 并且是骨骼肌修复和再生不可或缺的贡献者。自从建立我的 独立实验室，我们在了解消瘦如何相关方面取得了重大进展 影响卫星/肌肉干细胞（SC）生物学的因素，我们有能力探索其机制和 感染性休克后肌肉功能障碍的代谢基础。本文提出的大局问题 MIRA/R35 应用是：败血症相关因素如何影响 SC 功能？该提案强调了三点 我们正在开发的项目领域使用不​​同的实验和概念来解决这个核心问题 策略。首先，我们将探讨脓毒症相关细胞因子如何调节 SC 代谢。我们发现肌肉 消耗/恶病质相关细胞因子可以增强参与调节能量代谢的途径 并提出确定脓毒症相关细胞因子暴露对 SC 脂质代谢的影响。第二， 我们将研究脓毒症相关代谢物影响 SC 功能的机制。我们呈现 有证据表明与消耗相关的代谢物可以拮抗干细胞分化，并提出 研究以下假设：其中一些脓毒症代谢生物标志物也具有生物活性 能够增强 SC 激活的信号分子。第三，我们将利用尖端代谢组学 分析从小鼠脓毒症模型中分离出的肌肉干细胞，以确定相关的代谢特征 败血症发作并延长恢复时间。我们证明 SC 可以表现出持续的代谢改变 急性代谢紊乱并提出败血症相关的代谢紊乱会损害 SC 代谢网络长期进入恢复期。这三个拟议项目领域得到了以下机构的支持： 过去严格的干细胞生物学培训、梅奥诊所充满活力的研究和临床环境，以及 来自经验丰富的教师导师的持续专业支持和指导。总体来说顺利完成 拟议的 MIRA/R35 奖项将： a) 促进建立一个动态的、独立的、成本低廉的 梅奥诊所以 NIGMS 为重点的高效初级教师研究项目，b) 增进我们对 干细胞如何响应和适应脓毒症相关因素，以及 c) 推动长期脓毒症领域的发展 管理进入新的和尚未开发的领域，例如干细胞操作和代谢 重新编程。