HMGB1 Mediates the Onset of Loading-Induced Tendon Injury

HMGB1 介导负荷引起的肌腱损伤的发生

基本信息

批准号：
9318431
负责人：
JAMES H-C. WANG
金额：
$ 17.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318431
关键词：
Adverse effects Affect American Athletic Binding Proteins Biological Assay Biological Models Biological Process Cell Proliferation Cells Cellular Stress Chronic Clinic Clinical Collagen Fiber DNA-Binding Proteins Development Dinoprostone Enzyme-Linked Immunosorbent Assay Enzymes Event Exposure to Fibroblasts Frequencies Gene Expression General Population Glycyrrhizic Acid HMGB1 Protein Healthcare Hemorrhage Immune Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Injury Interstitial Collagenase Kidney Kidney Failure Lead Leukocytes Liver Lung Mammalian Cell Measures Mechanical Stress Mechanics Mediating Modeling Molecular Molecular Analysis Mus Muscle Nuclear Nucleosomes Occupational Organ PECAM1 gene PTGS2 gene Patients Pattern Periodontal Ligament Pharmacotherapy Prevention strategy Production Protocols documentation Recruitment Activity Reporting Research Role Running Signal Transduction Signaling Molecule Site Sports Staining method Stains Sterility Stress Stromelysin 1 Structure Tendinopathy Tendon Injuries Tendon structure Testing Tissue Inhibitor of Metalloproteinase-1 Tissues Translations Trauma Ulcer Western Blotting angiogenesis bone cell injury collagenase 3 cost extracellular in vitro Model in vivo inhibitor/antagonist injured innovation macrophage mechanical force mechanical load novel palliative prevent response treadmill treatment strategy young adult

项目摘要

Tendon injuries affect millions of Americans in both occupational and athletic settings and cost billions of healthcare dollars every year. While mechanical loading is considered as a major causative factor responsible for tendon injuries, the molecular mechanisms that initiate translation of mechanical loading into tendon injuries remain unknown. In this study, we offer an innovative hypothesis that HMGB1, a well-established inflammation-related nuclear binding protein in major tissues and organs, is responsible for the onset of the tendon inflammatory cascade due to excessive mechanical loading placed on tendons. Specifically, we propose two aims in this study: 1) to determine the effects of various mechanical loading conditions on tendon cells using a novel in vitro model system; and 2) to determine the effects of mechanical over-loading conditions on mouse tendons in vivo using a well-established mouse treadmill running model. Cellular and molecular analyses will be performed to define the HMGB1 signaling cascade. This study represents the first efforts to determine the role of HMGB1 in the onset of tendon injuries. The successful completion of this study will reveal the early signaling mechanism that is responsible for the development of full blown tendinopathy often seen down-the-road in tendinopathic patients. This research endeavor will lead to new prevention and treatment strategies such as targeting HMGB1 by blocking its action that will be more effective than current tendinopathy treatment options, which are largely palliative.

肌腱受伤会在职业和运动环境中影响数百万美国人，并造成数十亿美元每年的医疗保健美元。虽然机械负载被认为是负责的主要病因因素对于肌腱损伤，将机械负荷转换为肌腱损伤的分子机制仍然未知。在这项研究中，我们提供了一个创新的假设，即HMGB1是一个完善的主要组织和器官中与炎症相关的核结合蛋白是负责的肌腱炎症级联反应是由于肌腱上的机械负荷过多而引起的。具体来说，我们在这项研究中提出了两个目标：1）确定各种机械加载条件对肌腱的影响使用新型体外模型系统的细胞； 2）确定机械过载条件的影响在鼠标腱上使用良好的鼠标跑步机模型在体内。细胞和分子将进行分析以定义HMGB1信号级联。这项研究代表了确定HMGB1在肌腱损伤发作中的作用的首次努力。这这项研究的成功完成将揭示负责的早期信号传导机制肌腱疗法患者经常会出现全部肌腱病的发育。这项研究努力将导致新的预防和治疗策略，例如通过阻止其行动来瞄准HMGB1 这将比当前的肌腱病治疗方案更有效，后者在很大程度上是姑息治疗的。