Targeting Collagen Mechanical Damage using Collagen Hybridizing Peptides

使用胶原蛋白杂交肽针对胶原蛋白机械损伤

基本信息

批准号：
10158440
负责人：
JEFFREY A. WEISS
金额：
$ 36.65万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-05 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158440
关键词：
Affinity Amino Acids Binding Biomechanics Cartilage Cartilage injury Clinical Collagen Collagen Fibril DNA Degenerative polyarthritis Dense Connective Tissue Detection Development Diffusion Digestion Disease Elements Evolution Exhibits Experimental Models Fatigue Fissural Future Goals Hybrids In Situ Inflammatory Response Injury Kinetics Label Ligaments Mechanical Stress Mechanics Methods Molecular Molecular Probes Molecular Target Musculoskeletal Musculoskeletal Diseases Nature Outcomes Research Pain Penetration Peptide Hydrolases Peptides Predisposition Process Protocols documentation Reaction Reporting Research Rotator Cuff Sensitivity and Specificity Specimen Stains Stress Structure Techniques Technology Tendinopathy Tendon structure Time Tissues Trypsin Weight-Bearing state Work articular cartilage base carboxyfluorescein cell injury clinically relevant clinically significant detection method disability enthalpy experimental study fluorophore improved in vivo monitoring insight macrophage mechanical load mechanical properties melting musculoskeletal injury next generation novel novel diagnostics novel therapeutics response soft tissue synthetic peptide targeted delivery targeted treatment

项目摘要

SUMMARY Detection of Collagen Mechanical Damage using Collagen Hybridizing Peptides. Mechanical injury to load-bearing tissues leads to many clinically significant conditions (e.g. tendinosis, rotator cuff disease) but we have limited understanding of the injury process of tissues that are damaged by mechanical stress. The overall goal of the proposed research is to gain new understanding of the biomechanics of load bearing collagenous tissues by developing the collagen hybridizing peptide (CHP) technology into a new mechanical damage detection method. CHP has been reported to bind to denatured collagen strands originating from protease activity or by mechanical damage in a manner similar to primer binding to melted DNA during PCR. We propose to substantially expand the capabilities of CHP damage detection by developing new CHPs that are smaller for faster diffusion into dense musculoskeletal tissues and exhibit accelerated binding kinetics to allow faster damage reporting. We will also develop a new CHP that only fluoresces upon binding with collagen, eliminating the need to stain and wash tissues and enabling the CHP to serve as a damage gauge in overloaded tissues. We will then develop optimized protocols for the use of the existing and new CHPs, determine the relationship between collagen fibril strain and CHP binding in musculoskeletal soft tissues, and quantitatively compare CHP targeting to other techniques. Finally, we will apply CHP targeting to elucidate the relationship between tissue level mechanical loading and mechanical damage to collagen at the molecular level. We will focus on two important musculoskeletal tissues of considerable clinical relevance: tendons and articular cartilage. Considering the wide-spread impact of collagen damage in musculoskeletal injuries and diseases, in- depth understanding of the relationships between molecular level collagen damage and mechanical overloading will provide new insights into the biomechanics of load-bearing tissues as well as help develop new diagnostics and therapies for managing musculoskeletal disorders.

概括使用胶原蛋白杂交肽检测胶原蛋白机械损伤。对负荷组织的机械损伤导致许多临床上的重要条件（例如肌腱病，旋转器袖口疾病），但我们对机械损坏的组织的损伤过程有限压力。拟议研究的总体目标是对负载的生物力学有了新的了解通过将胶原蛋白杂交肽（CHP）技术开发为新的胶原组织机械损伤检测方法。据报道，CHP与成型的胶原蛋白链结合起来从蛋白酶活性或机械损伤中以类似于底漆与融化DNA结合的方式进行 pcr。我们建议通过开发新的CHP来大大扩大CHP损伤检测的能力较小的，可以更快地扩散到密集的肌肉骨骼组织中，并表现出加速的结合动力学允许更快的损坏报告。我们还将开发一种新的CHP，仅在与胶原蛋白结合后才荧光，消除需要染色和洗涤组织并使CHP充当损伤量表的需求组织。然后，我们将开发使用现有和新CHP的优化协议，确定肌肉骨骼软组织中胶原蛋白原纤维应变与CHP结合之间的关系，并定量将CHP靶向与其他技术进行比较。最后，我们将应用CHP定位以阐明关系在组织水平的机械负荷和分子水平胶原蛋白的机械损伤之间。我们将专注于两个重要的临床相关性的两个重要的肌肉骨骼组织：肌腱和关节软骨。考虑到胶原蛋白损伤对肌肉骨骼损伤和疾病的广泛影响，深度了解分子水平胶原蛋白损伤与机械超载之间的关系将为负载组织的生物力学提供新的见解，并有助于开发新的诊断和管理肌肉骨骼疾病的疗法。