Functional role of skeletal muscle in the innate immune response to sepsis

骨骼肌在脓毒症先天免疫反应中的功能作用

• 批准号: 9306141
• 负责人: THOMAS Lindsay CLANTON
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306141
• 关键词: Acute-Phase Proteins; Adaptor Signaling Protein; Adult; Amino Acids; Animals; Atrophic; Blood Circulation; Blood Vessels; Blood flow; Body Weight; Bone Marrow; Cell Proliferation; Cells; Cessation of life; Coagulation Process; Complex; Critical Care; Data; Death Rate; Development; Dietary Intervention; Diffuse; Effectiveness; Endocrine system; Exercise; Failure; General Population; Goals; Health; Homeostasis; Hospitals; Host Defense; Immune; Immune response; Immune system; Immunologic Memory; Individual; Infection; Inflammatory; Innate Immune Response; Intensive Care; Interleukin 6 Receptor; Interleukin-6; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Life; Lipopolysaccharides; Liver; Mediating; Medicare; Medicine; Membrane; Modeling; Molecular; Muscle; Muscle Development; Muscular Atrophy; Mutation; Myelogenous; Natural Immunity; Organ; Organism; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Play; Prevention strategy; Production; Protein Biosynthesis; Protein Isoforms; Protein Secretion; Proteins; Receptor Activation; Receptor Signaling; Recording of previous events; Recovery; Recruitment Activity; Research; Research Personnel; Resolution; Role; Scientist; Sepsis; Sepsis Syndrome; Septic Shock; Series; Signal Transduction; Skeletal Muscle; Survival Rate; Systemic infection; Testing; Time; Tissues; Toll-like receptors; Transgenic Mice; activation-induced cytidine deaminase; chemokine; cytokine; effective therapy; exercise intervention; fighting; immunoregulation; mortality; mouse model; novel; pathogen; protein expression; protein metabolism; public health relevance; receptor; receptor-mediated signaling; rehabilitation strategy; response; sedentary lifestyle; septic; skeletal muscle wasting; tool; trafficking; treatment strategy

 DESCRIPTION (provided by applicant): "Functional role of skeletal muscle in the innate immune response to sepsis" Septic shock is one of the most common yet difficult-to-manage conditions in intensive care. Old or frail patients suffer mortality rates of 30-40%, yet only 4-5% of otherwise healthy adults die. We hypothesize that a key to understanding the effectiveness of defense against septic shock in a given individual may lie in the health and immunoresponsiveness of their skeletal muscles. If true, then novel exercise and nutritional interventions or targeting membrane receptors on muscle may prove effective treatment or prevention strategies. Though the immune responses of skeletal muscle have been known for decades, their specific contribution to host defense has eluded scientists because of difficulty in isolating their net contribution. Our laboratories have developed new transgenic mice that provide the tools to approach this problem effectively for the first time. We provide strong preliminary data to suggest that the influence of skeletal muscle on the response to infection may be strong enough to cause a major shift in our understanding of innate immunity. AIM 1: To determine the contribution of skeletal muscle toll like receptor (TLR) activation on innate immune responsiveness and muscle atrophy in polymicrobial sepsis. The approach to this aim is to study the response to septic shock in conditional transgenic mice that have had an adapter protein for TLRs (Myd88) knocked out in adult skeletal muscle. The importance of this protein in response to infection is made clear by the fact that animals expressing no Myd88 have no cytokine responses to septic shock. We will determine how this mutation in muscle changes the cytokine response profiles over time, the pattern of immune cell trafficking in the circulation and in targeted organs, the extent of tissue damage, the extent of muscle atrophy, acute phase protein expression and the rate of survival. Results will be compared to mutation where Myd88 has been knocked out of inflammatory cells. We will also evaluate whether well-known exercise-induced protection in septic shock operates through changes in immune responsiveness via muscle TLR activation. AIM 2: To determine the contribution of skeletal muscle IL-6 on innate immune responsiveness and development of muscle atrophy in polymicrobial sepsis. IL-6 has a unique role to play in muscle responses to infection. First it is one of the most predominant cytokines secreted by muscle in response to pathogens. Secondly, it is the primary endocrine system responsible for stimulation of acute phase protein secretion in liver and other organs, and it may be an important player in development of atrophy during sepsis. Using a new inducible muscle specific IL-6 knockout mouse, we will determine the contribution of skeletal muscle IL-6 to the overall pattern of host defense, inflammatory cell trafficking, cytokine expression, atrophy, acute phase protein production, organ damage and mortality. In addition, by comparing results with another muscle specific knockout of IL-6 receptor activity, we will determine if the atrophy and acute phase protein responses of muscle in sepsis are due to IL-6 receptor mediated signaling on muscle.

 描述（由申请人提供）：“骨骼肌在脓毒症先天免疫反应中的功能作用”脓毒性休克是重症监护中最常见但难以管理的疾病之一。年老体弱的病人死亡率高达30- 40%， 健康的成年人死亡。我们假设，了解特定个体感染性休克防御有效性的关键可能在于骨骼肌的健康和免疫反应性。如果是真的，那么新的运动和营养干预或靶向肌肉膜受体可能证明是有效的治疗或预防策略。虽然骨骼肌的免疫反应已经知道了几十年，但它们对宿主防御的具体贡献一直困扰着科学家，因为难以确定它们对宿主防御的作用。 分离出他们的净贡献。我们的实验室已经开发出新的转基因小鼠，首次为有效解决这一问题提供了工具。我们提供了强有力的初步数据，表明骨骼肌对感染反应的影响可能足以引起我们对先天免疫理解的重大转变。目标1：目的：探讨骨骼肌Toll样受体（TLR）激活对多菌性脓毒症患者先天免疫应答和肌肉萎缩的影响。这个目标的方法是研究条件转基因小鼠对感染性休克的反应，这些小鼠在成年骨骼肌中敲除了TLR的衔接蛋白（Myd 88）。这种蛋白质在感染应答中的重要性通过不表达Myd 88的动物对败血性休克没有细胞因子应答的事实而清楚地表明。我们将确定肌肉中的这种突变如何随时间改变细胞因子反应谱，免疫细胞在循环中的运输模式， 在靶器官中，组织损伤程度、肌肉萎缩程度、急性期蛋白表达和存活率。将结果与其中Myd 88已从炎性细胞中敲除的突变进行比较。我们还将评估是否众所周知的运动诱导的保护在感染性休克通过肌肉TLR激活的免疫反应性的变化。目标2：确定骨骼肌IL-6在多微生物脓毒症中对先天免疫应答和肌肉萎缩发展的作用。IL-6在肌肉对感染的反应中起着独特的作用。首先，它是肌肉响应病原体分泌的最主要的细胞因子之一。其次，它是负责刺激肝脏和其他器官中急性期蛋白分泌的主要内分泌系统，并且它可能是脓毒症期间萎缩发展的重要参与者。使用一种新的可诱导的肌肉特异性IL-6基因敲除小鼠，我们将确定骨骼肌IL-6对宿主防御、炎性细胞运输、细胞因子表达、萎缩、急性期蛋白产生、器官损伤和死亡率的整体模式的贡献。此外，通过与另一种肌肉特异性敲除IL-6受体活性的结果进行比较，我们将确定脓毒症中肌肉的萎缩和急性期蛋白反应是否是由于肌肉上的IL-6受体介导的信号传导。