Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness

细胞和身体功能结果导致危重疾病后肌肉恢复失败

基本信息

批准号：
10523782
负责人：
Kirby P Mayer
金额：
$ 14.91万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523782
关键词：
Acute respiratory failure Address Adult Applied Research Basic Science Biogenesis Biopsy COVID-19 Cell fusion Cell physiology Cells Characteristics Clinical Clinical Investigator Clinical Sciences Clinical Trials Complex Critical Illness Data Deuterium Oxide Development Disabled Persons Environment Functional disorder Future Gait speed Goals Grant Health Hospitalization Hospitals Human Immunohistochemistry Impairment Inflammatory Intensive Care Units Intervention Knowledge Label Lead Learning Lower Extremity Measures Mechanical ventilation Mentors Mentorship Methodology Microscopy Mitochondria Mitochondrial Proteins Morphology Muscle Muscle Fatigue Muscle Proteins Muscle Weakness Muscle function Muscle satellite cell Outcome Patient-Focused Outcomes Patients Pattern Performance Pharmacology Phase Phenotype Physical Function Physical Rehabilitation Property Protein Biosynthesis Proteins Proteolysis Quality of life RNA Recovery Recovery of Function Regression Analysis Rehabilitation therapy Research Research Training Respiration Ribosomes Sepsis Severity of illness Skeletal Muscle Stable Isotope Labeling Statistical Data Interpretation Survivors Technical Expertise Testing Time Training Translating Walking Western Blotting cell type disability effective therapy experimental study functional disability functional outcomes improved inflammatory milieu longitudinal analysis macrophage muscle form muscle strength novel patient subsets physically handicapped prevent protein degradation proteostasis rehabilitation research rehabilitation strategy satellite cell skeletal muscle wasting skills stem

项目摘要

Project Summary Survival of critical illness such as sepsis and acute respiratory failure is accompanied by serious physical complications with many patients acquiring long-term impairments. Mechanisms and factors that impede the recovery of muscle size and function after hospitalization are not understood. It is unclear if recovery after critical illness leads to a subsequent deficiency in the ability to make new proteins (protein synthesis) or if a catabolic/inflammatory environment persists preventing muscle regrowth which involves muscle stem cell (satellite cell) fusion to myofibers. We will address gaps in knowledge by studying skeletal muscle proteostasis, cellular environment, and RNA and mitochondrial biogenesis after critical illness with closely aligned physical function outcomes. Understanding the cellular environment in the period after hospital release, and how it impacts muscle protein turnover will direct efforts to effective therapies to accelerate muscle regrowth. The overall goal of this application is to identify cellular properties of muscle that may contribute to long-term physical disability in survivors of critical illness. Overall, I hypothesize that aberrant cellular processes in muscle are underlying prolonged functional impairments in patients after critical illness. In Aim 1, we will determine the longitudinal trajectory of muscle and physical function recovery and establish muscle morphological and cellular characteristics in patients after critical illness. We hypothesize that patients with higher severity of illness in the ICU and with longer duration of mechanical ventilation will have the most persistent muscle weakness and deficits in muscle power in recovery. In Aim 2, we will identify cellular mechanisms that contribute to muscle dysfunction after critical illness. We hypothesize that patients with persistent muscle weakness and fatigue have impaired mitochondrial function compared to controls. Moreover, we hypothesize that survivors of critical illness have elevated myofibrillar protein synthesis and ribosome biogenesis in early recovery, but muscle regrowth does not occur due to elevated proteolysis. The overarching goal of this proposal focuses on elucidating the factors that lead to muscle mass dysregulation in recovery and inform why some patients develop persistent disability and others gradually improve. The proposed mentoring team provides the knowledge and training to develop into an independent clinical investigator integrating basic and applied science. The proposed training plan in Aim 1 emphasizes clinical trial methodologies and complex longitudinal analyses. For aim 2, the training focuses on skeletal muscle experiments; specifically, knowledge to assess muscle proteostasis, mitochondrial content and function, and muscle morphology. I will learn the technical skills to examine skeletal muscle including stable isotope labeling, immunohistochemistry, western blot analysis, and microscopy will be gained. Moreover, the proposed research and training plan provides the necessary training and mentorship to translate findings in this proposal into the development of targeted rehabilitation and pharmacological interventions in future R01 studies.

项目摘要败血症和急性呼吸衰竭等重症疾病的生存伴随着严重许多患者的身体并发症患有长期障碍。机制和因素阻碍了住院后肌肉大小和功能的恢复。目前尚不清楚是否危害疾病后的恢复会导致生产新蛋白质的能力不足（蛋白质合成）或分解代谢/炎症环境是否持续阻止肌肉再生肌肉干细胞（卫星细胞）与肌纤维融合。我们将通过研究骨骼来解决知识的差距肌肉蛋白质抑制剂，细胞环境，RNA和线粒体生物发生后，重病紧密对齐的身体功能结果。了解医院后期的细胞环境释放及其影响肌肉蛋白周转率如何将努力引导至有效的疗法以加速肌肉再生。该应用的总体目标是确定肌肉的细胞特性危害疾病幸存者的长期身体残疾。总的来说，我假设这种异常肌肉中的细胞过程是严重疾病后患者的长时间功能障碍。在 AIM 1，我们将确定肌肉和身体功能恢复的纵向轨迹，并建立疾病后患者的肌肉形态和细胞特征。我们假设患者在ICU中，疾病的严重程度较高，机械通气持续时间更长的疾病将具有最大的疾病持续的肌肉无力和肌肉力量的缺陷。在AIM 2中，我们将确定蜂窝危害病后导致肌肉功能障碍的机制。我们假设患有与对照组相比，持续的肌肉无力和疲劳受损的线粒体功能。而且，我们假设危害疾病的幸存者升高了肌原纤维蛋白的合成和核糖体早期恢复中的生物发生，但是由于蛋白水解升高而不会发生肌肉再生。总体该提案的目标重点是阐明导致肌肉质量失调和恢复和告知为什么某些患者会持续性残疾，而另一些患者会逐渐改善。拟议的指导团队提供知识和培训，以发展为独立的临床研究者，以整合基本和应用科学。 AIM 1中提出的培训计划强调临床试验方法和复杂纵向分析。对于AIM 2，训练着重于骨骼肌实验。具体而言，知识评估肌肉蛋白质抑制，线粒体含量和功能以及肌肉形态。我会学习检查骨骼肌的技术技能，包括稳定的同位素标签，免疫组织化学，西方印迹分析和显微镜将获得。此外，拟议的研究和培训计划提供了必要的培训和指导，将此提案中的发现转化为有针对性的发展未来R01研究中的康复和药理干预措施。