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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：
10437626
负责人：
JEFFREY A. WEISS
金额：
$ 35.54万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437626
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.

总结使用胶原杂交肽检测胶原机械损伤。承重组织的机械性损伤导致许多临床上显著的病症（例如，肌腱病、旋转器但我们对机械损伤组织的损伤过程了解有限，应力这项研究的总体目标是对负荷的生物力学有新的认识通过将胶原杂交肽（CHP）技术发展成为一种新的机械损伤检测方法据报道，CHP结合变性胶原蛋白链，通过蛋白酶活性或通过机械损伤，以类似于引物结合到熔化的DNA的方式， PCR法我们建议通过开发新的CHP来大大扩展CHP损坏检测的能力其较小，以便更快地扩散到致密的肌肉骨骼组织中，并表现出加速的结合动力学，更快地报告损坏情况。我们还将开发一种新的CHP，仅在与胶原蛋白结合时才会发出荧光，消除了对染色和清洗组织的需要，并使CHP能够在过载时用作损伤测量仪，组织中然后，我们将为现有和新的CHP的使用开发优化的协议，确定肌肉骨骼软组织中胶原纤维应变与CHP结合之间的关系，并定量将CHP定位与其他技术进行比较。最后，我们将应用CHP靶向来阐明这种关系组织水平的机械负荷和分子水平上对胶原的机械损伤之间的关系。我们将重点关注两个重要的肌肉骨骼组织的相当大的临床相关性：肌腱和关节软骨考虑到胶原蛋白损伤在肌肉骨骼损伤和疾病中的广泛影响，深入了解分子水平胶原蛋白损伤与机械过载之间的关系将为承重组织的生物力学提供新的见解，并有助于开发新的诊断方法。以及用于管理肌肉骨骼疾病的疗法。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Collagen fibrils from both positional and energy-storing tendons exhibit increased amounts of denatured collagen when stretched beyond the yield point.

当拉伸超过屈服点时，来自位置肌腱和储能肌腱的胶原原纤维表现出变性胶原蛋白的数量增加。

DOI：
10.1016/j.actbio.2022.11.018
发表时间：
2023
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Lin,AllenH;Slater,ChristopherA;Martinez,Callie-Jo;Eppell,StevenJ;Yu,SMichael;Weiss,JeffreyA
通讯作者：
Weiss,JeffreyA

Peptoid Residues Make Diverse, Hyperstable Collagen Triple-Helices.

DOI：
10.1021/jacs.1c00708
发表时间：
2021-07-28
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Kessler, Julian L.;Kang, Grace;Qin, Zhao;Kang, Helen;Whitby, Frank G.;Cheatham, Thomas E., III;Hill, Christopher P.;Li, Yang;Yu, S. Michael
通讯作者：
Yu, S. Michael

Load transfer, damage, and failure in ligaments and tendons.