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Investigation of Collagen as a Smart Engineering Material

胶原蛋白作为智能工程材料的研究

基本信息

批准号：
7230087
负责人：
Jeffrey W Ruberti
金额：
$ 16.77万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230087
关键词：
Affect American Animals Architecture Arthritis Binding Binding Sites Biological Assay Bos taurus Cartilage Cattle Cells Charge Collagen Collagen Fibril Collagen Type I Complex Controlled Environment Cornea Corneal Stroma Data Degenerative polyarthritis Development Diffusion Disease Economics Effectiveness Engineering Environment Enzyme Kinetics Enzymes Epigenetic Process Evolution Excision Extracellular Matrix Fibrillar Collagen Fibroblasts Glycosaminoglycans High temperature of physical object Homeostasis Hydroxyproline In Vitro Interstitial Collagenase Investigation Kinetics Life Light MMPI Matrix Metalloproteinases Mechanical Stimulation Mechanics Morphogenesis Object Attachment Pathology Patients Pattern Play Process Proline Quality of life Rate Research Personnel Resistance Review Literature Role Scanning Probe Microscopes Signal Transduction Stretching Testing Time Tissues Weight-Bearing state base bone collagenase collagenase 3 cost femur head in vivo insight monomer programs repaired research study response single molecule theories

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis alone disables 10% of Americans older than 60 and is estimated to cost the US economy more than $60 billion annually. Arthritis is just one example of a constellation of collagen-related diseases that severely affect the quality of life of patients. As the principle tensile load-bearing molecule in animals, collagen is responsible for our ability to interact with the mechanical world around us. The first metazoans were a direct result of the evolution of collagen nearly 800 million years ago. Prior to this time, life was restricted to the confines of a single cell. Collagen, a triple helical molecule comprising the sequence gly-x-y (where x and y are typically proline and hydroxyproline respectively), is the material that binds animals together. Consistent with this idea is the fact that fibrillar collagens (I, II, III, V and XI) are virtually always found in tension. Even in cartilage, where the applied compressive load is carried by the fixed charges on glycosaminoglycans, the type II collagen fibrils are loaded in tension. Fibrillar collagens have the remarkable ability to self-assemble both longitudinally and radially. They also possess high mechanical strength. However, in this proposal we suggest that the most important feature of fibrillar collagens is that they comprise the basic building blocks of a "smart" engineering material. Specifically, review of literature and our own preliminary data show that fibrillar collagen under a mechanical tensile load is more resistant than unloaded collagen to both high temperature denaturation and to bacterial collagenase degradation. If this is also true for matrix metalloproteinase (MMP) degradation, then collagen/MMP enzyme kinetics would be a function of strain. In short, collagen that is loaded or "in use" would be less likely to degrade when exposed to MMP. Thus, matrix adaptation to applied mechanical load could proceed in the presence of both catabolic and anabolic molecules. Fibroblasts would not then be required to "select" molecules for removal. The state of strain would determine the effectiveness of available enzymes. To test this hypothesis, acellular collagenous matrices with highly anisotropic organization and single molecules will be subjected to MMPs in the presence of varying mechanical loads. The pattern of fibrillar degradation in the bulk tissue and the rate of cleavage of the single molecules will be recorded. If collagen cleavage is a function of strain, then the implications for collagen genesis, homeostasis and disease are apparent.

描述（由申请人提供）：仅骨关节炎就使10%的60岁以上的美国人致残，估计每年给美国经济造成600多亿美元的损失。关节炎只是严重影响患者生活质量的胶原蛋白相关疾病的一个例子。作为动物中主要的拉伸承重分子，胶原蛋白负责我们与周围机械世界相互作用的能力。第一个后生动物是近8亿年前胶原蛋白进化的直接结果。在此之前，生命被限制在单个细胞的范围内。胶原蛋白是一种包含序列gly-x-y（其中x和y通常分别为脯氨酸和羟脯氨酸）的三螺旋分子，是将动物结合在一起的物质。与这一想法相一致的是，纤维状胶原蛋白（I、II、III、V和XI）几乎总是处于张力状态。即使在软骨中，其中所施加的压缩载荷由糖胺聚糖上的固定电荷承载，II型胶原原纤维也承受张力。纤维状胶原具有显著的纵向和径向自组装能力。它们还具有很高的机械强度。然而，在本提案中，我们认为纤维状胶原蛋白最重要的特征是它们构成了“智能”工程材料的基本构建块。具体而言，文献综述和我们自己的初步数据表明，在机械拉伸载荷下的纤维状胶原蛋白比未加载的胶原蛋白更耐高温变性和细菌胶原酶降解。如果基质金属蛋白酶（MMP）降解也是如此，那么胶原/MMP酶动力学将是应变的函数。简而言之，加载或“使用中”的胶原蛋白在暴露于MMP时不太可能降解。因此，基质适应所施加的机械负荷，可以在分解代谢和合成代谢分子的存在下进行。成纤维细胞将不需要“选择”去除的分子。菌株的状态将决定可用酶的有效性。为了验证这一假设，具有高度各向异性组织和单分子的脱细胞胶原基质将在不同机械载荷的存在下经受MMP。将记录大量组织中纤维降解的模式和单个分子的裂解速率。如果胶原裂解是应变的函数，那么对胶原生成、稳态和疾病的影响是显而易见的。