Regulation of Human Muscle Protein Metabolism Following Burn Injury

烧伤后人体肌肉蛋白质代谢的调节

基本信息

批准号：
8060986
负责人：
Edward Kelly Merritt
金额：
$ 4.84万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-10 至 2013-01-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8060986
关键词：
70-kDa Ribosomal Protein S6 Kinases Acute Adult Affect Age Amino Acids Apoptosis Atrophic Automobile Driving Bed rest Blood Circulation Body Surface Area Burn injury Cachexia Calcium Calpain Caspase Catabolism Cell Proliferation Cells Chronic Obstructive Airway Disease Clinical Communities Complex Data Degradation Pathway Development Disease End stage renal failure Event Growth HIV Healed Hormones Human Impaired wound healing In Vitro Infection Inflammatory Injury Insulin Resistance Knowledge Lead Limb structure Malignant Neoplasms Measures Mediating Metabolic Mind Molecular Morbidity - disease rate Muscle Muscle Fibers Muscle Proteins Muscular Atrophy Myoblasts Myopathy Pathway interactions Patients Phase Physiological Process Protein Biosynthesis Proteins Recovery Regulation Research Personnel Research Project Grants Resolution Risk Sampling Scientist Series Serum Severities Signal Pathway Signal Transduction Signaling Protein Site Skeletal Muscle Staging System Testing Translation Initiation Translations Treatment Efficacy Ubiquitin computerized data processing cytokine experience healing human FRAP1 protein hypercortisolemia injured interest mortality multicatalytic endopeptidase complex muscle form prevent protein degradation protein metabolism regenerative research study response satellite cell sex therapy development wasting wound

项目摘要

DESCRIPTION (provided by applicant): Severe burn injury leads to a hypercatabolic state that lasts for up to one year and results in the dramatic loss of skeletal muscle mass. The accelerated protein loss contributes to what is likely the most rapid rate of muscle degradation and subsequent muscle atrophy observed. The loss of lean body mass increases the patient's risk for infection and impairs wound healing. While it is well accepted that prolonged skeletal muscle catabolism occurs due to burn injuries in humans, the molecular events underlying this have yet to be elucidated. Also unknown is why skeletal muscle atrophy persists even after the patient's burn wounds have "healed." To answer these questions, serum and muscle samples will be obtained from subjects burned over 20-60% of total body surface area and compared to those from matched controls. Burn samples will be obtained four to ten days post-burn injury and again six to nine months post-burn injury after injuries have healed. Muscle samples will be tested to determine the activation of molecular signaling pathways involved in muscle protein synthesis and degradation. Determination of which protein synthesis and degradation pathways are upregulated or suppressed during the recovery process is crucial to understanding how to minimize post-burn muscle loss. To isolate the effects of the burn milieu on skeletal muscle, an in vitro system will be used. Serum from burn subjects in the early and late stages of recovery will be applied to healthy, human skeletal muscle cells. Various markers of muscle growth and protein metabolism will be measured to determine the effect of burn-serum on healthy skeletal muscle. The results obtained from these in vitro experiments will determine how circulating factors such as inflammatory cytokines affect remote skeletal muscle catabolism. After completion of these studies, a better understanding of burn-induced muscle atrophy will exist. This research project holds an extremely high degree of scientific impact for scientists and doctors within the burn community as well as researchers interested in skeletal muscle atrophy. It must be emphasized that treatment efficacy will not be achieved without first having a better understanding of the underlying mechanisms leading to muscle protein losses in these patients. The research project described will provide important mechanistic data that are expected to markedly influence the approach to treating human muscle atrophy consequent to burn injury. PUBLIC HEALTH RELEVANCE: During recovery from severe burn injury, a dramatic loss of skeletal muscle occurs throughout the body. These studies will help us understand the molecular and cellular aspects that lead to this muscle loss. Understanding the mechanisms controlling muscle loss after burn will allow for the development of treatments to prevent it.

描述（由申请人提供）：严重的烧伤会导致持续一年的超代代谢状态，并导致骨骼肌质量的巨大损失。加速的蛋白质损失有助于肌肉降解和随后观察到的肌肉萎缩最快的速度。瘦体重的丧失会增加患者感染的风险并损害伤口愈合。虽然人们很公认的是，由于人类的烧伤受伤而发生了长时间的骨骼肌分解代谢，但尚未阐明了这一点的分子事件。同样未知的是为什么即使患者的烧伤“愈合”，骨骼肌萎缩仍然存在。为了回答这些问题，将从捕入总体表面积的20-60％以上的受试者中获得血清和肌肉样本，并与匹配对照组的受试者进行比较。燃烧样品将在烧伤后四到十天，在受伤后烧伤后六到九个月后再次获得烧伤样品。将测试肌肉样品，以确定参与肌肉蛋白质合成和降解的分子信号传导途径的激活。在恢复过程中，确定哪些蛋白质合成和降解途径被上调或抑制对于理解如何最大程度地减少燃烧后肌肉损失至关重要。为了隔离烧伤环境对骨骼肌的影响，将使用体外系统。在恢复的早期和晚期，烧伤受试者的血清将应用于健康的人类骨骼肌细胞。将测量肌肉生长和蛋白质代谢的各种标志物，以确定烧伤对健康骨骼肌的影响。从这些体外实验获得的结果将决定循环因子如何影响远程骨骼肌分解代谢。完成这些研究后，将存在对燃烧引起的肌肉萎缩的更好理解。该研究项目对烧伤社区中的科学家和医生以及对骨骼肌肉萎缩感兴趣的研究人员具有极高的科学影响。必须强调的是，如果不先更好地了解导致这些患者肌肉蛋白质损失的潜在机制，就无法实现治疗效率。所描述的研究项目将提供重要的机械数据，这些数据有望显着影响治疗人类肌肉萎缩而导致烧伤损伤的方法。公共卫生相关性：在严重的烧伤中恢复期间，骨骼肌造成了巨大的损失。这些研究将有助于我们了解导致肌肉损失的分子和细胞方面。了解燃烧后控制肌肉损失的机制将允许开发治疗以防止这种治疗方法。