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 败血症是在重症监护环境中通常遇到的一种威胁生命的疾病。尽管 临床败血症管理的进步降低了急性败血症死亡率，越来越多 严重的败血症幸存者发展到慢性病状态。确实，许多幸存者报告了持续的肌肉 弱点，呼吸困难和认知能力下降，因为其后生活中的并发症使并发症变得衰弱。我们 假设管理败血症长期效应的关键是了解与败血症相关的方式 循环因子会影响长寿特异性干细胞的代谢状态。鉴于发病率很高 在七个后肌肉功能障碍中，我们建议最初评估急性和持续的代谢缺陷 骨骼肌干细胞。在成年骨骼肌中，卫星细胞是主要的居民干细胞种群 并且是骨骼肌修复和再生的不可或缺的贡献者。自建立我的 独立的实验室，我们已经取得了重大进展，以了解如何浪费如何相关 因素损害了卫星/肌肉干细胞（SC）生物学，我们有好处探索机械和 化粪池休克后肌肉功能障碍的代谢基础。这是提出的大图问题 MIRA/R35应用是：败血症相关因素如何影响SC功能？该提议突出了三个 我们正在开发的项目领域，可以使用独特的实验和概念来解决这个中心问题 策略。首先，我们将探讨败血症相关的细胞因子如何调节SC代谢。我们发现肌肉 浪费/缓存相关的细胞因子可以增加与调节能量代谢有关的途径 并建议定义败血症相关的细胞因子暴露对SC中脂质代谢的影响。第二， 我们将研究败血症相关代谢物影响SC功能的机制。我们在场 浪费相关代谢产物可以拮抗干细胞分化并提出的证据 调查了这些败血症代谢生物标志物中的一些也是生物活性的假设 能够增强SC激活的信号分子。第三，我们将利用最先进的代谢组学 从鼠败血症模型中分离出的肌肉干细胞的分析，以定义相关的代谢特征 随着败血症的发作和扩展恢复。我们表明，SC可以表现出持续的代谢改变 急性代谢破坏并提出败血症相关的代谢扰动损害SC 代谢网络长期进入恢复期。这三个提议的项目领域得到了 严格的干细胞生物学培训，梅奥诊所的充满活力的研究和临床环境，以及 经验丰富的教师导师的持续专业支持和指导。总体而言，成功完成 在拟议的MIRA/R35奖励中，将：a）促进建立动态，独立和成本 - 梅奥诊所的高效诺格姆斯初级教师研究计划，b）提高我们对 干细胞如何反应并适应与败血症相关的因素，c）驱动长期败血症的领域 管理进入新的和未经忽视的区域，例如干细胞操纵和代谢 重新编程。