Collagen Cross-linking in Skeletal Aging and Disease

骨骼衰老和疾病中的胶原蛋白交联

基本信息

批准号：
8502429
负责人：
David R Eyre
金额：
$ 32.01万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-07-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502429
关键词：
Adult Age Aging Arginine Biochemical Markers Biological Assay Biological Markers Bone Density Bone Resorption Cartilage Chemistry Clinical Collagen Collagen Type I Collagen Type III Degenerative polyarthritis Disease Environmental Risk Factor Failure Fibril-Associated Collagens Fibrillar Collagen Generations Genetic Goals Health Histidine Human Imines Individual Joints Link Location Longevity Mass Spectrum Analysis Measures Methods Molecular Molecular Target Monitor Nature Osteogenesis Imperfecta Osteoporosis Pathway interactions Patients Peptides Pharmaceutical Preparations Property Protein-Lysine 6-Oxidase Proteins Proteomics Public Health Pyrroles Reaction Risk Risk Factors Role Scientific Advances and Accomplishments Skeleton Structure Techniques Testing Thinking Tissues Urine Vertebrates adduct articular cartilage base bone bone quality clinically significant crosslink gene environment interaction indexing interest meetings molecular site novel osteoporosis with pathological fracture public health relevance pyridinoline skeletal skeletal tissue theories urinary

项目摘要

DESCRIPTION (provided by applicant): We are studying how collagen cross-links have evolved to adapt human bone, cartilage and other supporting tissues for their distinctive functions. We have raised the structure which predicts a novel chemistry and critical role for pyrrole cross-links in bone collagen and identified a previously unknown cross-link, arginoline, in cartilage collagen. We propose and will seek to validate a unified theory of oxidative maturation for cross-links in the fibrillar collagens of all tissues. Though the lysyl oxidase cross-linking mechanism was discovered in the 1970s, much is still unknown. Post-translational differences in collagen quality between individuals, notably in the cross-linking chemistry of bone and cartilages, are potential risk factors for osteoporotic fracture and joint failure. They result from cumulative environmental influences rather than a direct genetic basis. We are pursuing this through analyses of bone, cartilage and other skeletal tissue collagens using advanced mass spectrometric protein techniques. The clinical significance is the promise of new molecular targets in the effort to meet the public health challenges of osteoporosis and osteoarthritis. Skeletal tissues depend heavily on the cross-linking of highly specialized collagens for their unique strengths, properties and longevity. The translational aim, therefore, is to seek new molecular targets for therapy and non- invasive biomarkers based on urinary collagen peptides that can index a patient's bone quality, joint cartilage breakdown rate and other measures of skeletal health. PUBLIC HEALTH RELEVANCE: Using the power of protein mass spectrometry the goal is to complete a basic scientific understanding of how different skeletal collagens are covalently cross-linked. Qualitative differences in bone collagen cross-linking that develop with age and may to be linked to risk of osteoporotic fracture independent of bone density are of particular interest. In parallel with basic tissue studies, collagen fragments in urine are being examined by similar methods as potential non-invasive biomarkers of a patient's bone and joint health.

描述（由申请人提供）：我们正在研究胶原蛋白的交联是如何演变以适应人骨，软骨和其他支撑组织的独特功能。我们已经提高了结构，该结构预测了骨胶原蛋白中吡咯交联的新化学和关键作用，并在软骨胶原蛋白中鉴定了先前未知的交联Arginoline。我们提出并将寻求验证所有组织中纤维状胶原蛋白的交联的氧化成熟理论。尽管在1970年代发现了赖氨酸氧化酶的交联机制，但仍然尚不清楚。个体之间胶原蛋白质量的翻译后差异，尤其是在骨和软骨的交联化学中，是骨质疏松骨折和关节衰竭的潜在危险因素。它们是由累积环境影响而不是直接遗传基础引起的。我们通过使用晚期质谱蛋白技术对骨，软骨和其他骨骼组织胶原蛋白进行分析来追求这一点。临床意义是新的分子靶标在应对骨质疏松和骨关节炎的公共卫生挑战中的承诺。骨骼组织在很大程度上取决于高度专业的胶原蛋白的独特优势，特性和寿命。因此，转化的目的是基于尿胶原蛋白肽寻求新的分子靶标，用于治疗和非浸润性生物标志物，这些肽可以为患者的骨骼质量，关节软骨分解率和其他骨骼健康措施索引。公共卫生相关性：使用蛋白质质谱的力量，目标是完成对不同骨骼胶原蛋白如何共价交联的基本科学理解。随着年龄的增长而发展的骨胶原交联的定性差异，可能与骨质疏松骨折的风险有关，而与骨密度无关。与基本的组织研究并行，正在通过类似方法与患者骨骼和关节健康的潜在非侵入性生物标志物相似的方法进行了研究。