Collagen Diversity and Pathobiology in Skeletal Tissues

骨骼组织中的胶原蛋白多样性和病理生物学

• 批准号: 7989376
• 负责人: David R Eyre
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989376
• 关键词: 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; 2-oxoglutarate 3-dioxygenase proline; Adult; Affect; Amphibia; Architecture; Automobile Driving; Binding Sites; Biochemical Pathway; Biological Markers; Biology; Birds; Bone Diseases; Bone Matrix; Cartilage; Cattle; Cells; Characteristics; Collaborations; Collagen; Collagen Diseases; Collagen Fibril; Collagen Gene; Collagen Type I; Collagen Type II; Collagen Type III; Collagen Type IV; Collagen Type IX; Collagen Type V; Complex; Connective Tissue; Defect; Degenerative polyarthritis; Evolution; Failure; Fibrillar Collagen; Genes; Genetic; Genome; Goals; Histocompatibility Testing; Human; Hyaline Cartilage; Hydrogen Bonding; Hydroxylation; Intervertebral disc structure; Joints; Knowledge; Ligaments; Link; Mammals; Maps; Mass Spectrum Analysis; Mechanics; Meniscus structure of joint; Modification; Molecular; Molecular Chaperones; Multienzyme Complexes; Mus; Mutation; Osteogenesis Imperfecta; Pathogenesis; Pathway interactions; Phenotype; Phylogenetic Analysis; Play; Polymers; Population; Post-Translational Protein Processing; Prevention therapy; Process; Proline; Property; Protein Binding; Proteins; Regulation; Reptiles; Risk; Role; Series; Site; Skin; Source; Surface; Tendon structure; Testing; Tissue Differentiation; Tissues; Update; Vertebrates; Work; base; bone; cell type; clinically significant; crosslink; extracellular; human tissue; intervertebral disk degeneration; novel; osteoporosis with pathological fracture; public health relevance; skeletal disorder; skeletal dysplasia; skeletal tissue; therapeutic target; triple helix

DESCRIPTION (provided by applicant): In this competing renewal of AR036794 (title updated to reflect the evolution in specific aims and scope), we focus on a newly discovered mechanism of regulation of collagen fibril diversity that is important for understanding skeletal tissue differentiation and pathobiology. We have evidence that 3-hydroxproline (3Hyp) residues play a fundamental role in directing the manner of fibrillar collagen supramolecular assembly. The first hint came from our demonstration by mass spectrometry that the single, fully occupied 3Hyp site (P986) near the C-terminus of collagen a1(I) and a1(II) chains fails to be hydroxylated in collagens of the crtap mouse and recessive forms of human osteogenesis imperfecta (O.I.) caused by CRTAP or LEPRE1 mutations. We now have evidence for three classes of 3Hyp site in fibril-forming collagens. For example, a second site in type II collagen is highly hydroxylated in vitreous, meniscus and intervertebral disc but not in hyaline cartilage. The sequence motif of this second site is reproduced at D-periodic intervals in a2(V), with 3Hyp present, and shows similarities to a 3Hyp motif in type IV collagen. Tendon collagen uniquely contains a third type of 3Hyp motif, which we believe is characteristic and functionally important in tendon, ligament and related highly tensile tissues. Under 4 aims, we intend to pursue this concept aggressively since it is central to understanding how different cell types regulate the diversity of heteropolymeric collagen assemblies between different cartilages, bone, tendon and other connective tissues. If correct, it also has concept- changing implications for the field of vertebrate collagen biology. The clinical significance is in providing a molecular basis for understanding processes that cause cartilages and other collagenous tissues of low turnover to degenerate in the adult musculoskeleton in osteoarthritis, disc degeneration and related disorders of collagen framework failure. In addition, a full understanding of the effects of disrupting prolyl 3-hydroxylation in recessive forms of osteogenesis imperfecta we believe will reveal a molecular mechanism for brittle bone common to all forms of O.I. Such findings will also be significant for understanding qualitative changes in bone matrix that add significant risk of osteoporotic fracture in the population as a whole and a potential for novel biomarkers and therapeutic targets. PUBLIC HEALTH RELEVANCE: The goal is to understand molecular mechanisms that govern the diversity in properties of collagen, the protein that forms the structural framework of all major skeletal tissues in the body including bone, cartilages, tendons and ligaments. Specifically, we aim to define the biochemical pathways that equip bone collagen to mineralize, cartilage to last a lifetime as the bearing surfaces of joints and tendons and ligaments to transmit or restrain high mechanical loads without failing. With this knowledge new targets for therapy and prevention of genetic and acquired human disorders of bones and joints are predicted.

描述（由申请人提供）：在 AR036794 的竞争更新中（更新标题以反映特定目标和范围的演变），我们重点关注新发现的胶原纤维多样性调节机制，这对于理解骨骼组织分化和病理学非常重要。我们有证据表明 3-羟脯氨酸 (3Hyp) 残基在指导纤维状胶原超分子组装方式中发挥着重要作用。第一个提示来自我们通过质谱法的证明，即靠近胶原蛋白 a1(I) 和 a1(II) 链 C 末端的单个完全占据的 3Hyp 位点 (P986) 在 crtap 小鼠和隐性小鼠的胶原蛋白中未能被羟基化由 CRTAP 或 LEPRE1 突变引起的人类成骨不全症 (O.I.)。我们现在有证据表明原纤维形成胶原蛋白中存在三类 3Hyp 位点。例如，II 型胶原蛋白的第二个位点在玻璃体、半月板和椎间盘中高度羟基化，但在透明软骨中则不然。第二个位点的序列基序在 a2(V) 中以 D 周期间隔复制，存在 3Hyp，并且显示出与 IV 型胶原中的 3Hyp 基序的相似性。肌腱胶原蛋白独特地含有第三种类型的 3Hyp 基序，我们认为该基序在肌腱、韧带和相关高张力组织中具有特征性且具有重要的功能。在 4 个目标下，我们打算积极追求这个概念，因为它对于理解不同细胞类型如何调节不同软骨、骨骼、肌腱和其他结缔组织之间异聚胶原蛋白组件的多样性至关重要。如果正确的话，它也会对脊椎动物胶原蛋白生物学领域产生概念改变的影响。临床意义在于为理解导致成人肌肉骨骼中骨关节炎、椎间盘退变和胶原蛋白框架衰竭相关疾病中软骨和其他低周转胶原组织退化的过程提供分子基础。此外，充分了解破坏脯氨酰 3-羟基化对隐性成骨不全症的影响，我们相信将揭示所有类型 O.I. 所共有的脆骨分子机制。这些发现对于理解骨基质的质变也具有重要意义，骨基质的质变增加了整个人群骨质疏松性骨折的显着风险，并具有寻找新生物标志物和治疗靶点的潜力。 公共健康相关性：目标是了解控制胶原蛋白特性多样性的分子机制，胶原蛋白构成了体内所有主要骨骼组织（包括骨骼、软骨、肌腱和韧带）的结构框架。具体来说，我们的目标是定义使骨胶原矿化的生化途径，使软骨能够终生作为关节、肌腱和韧带的承载表面，以传递或抑制高机械负荷而不会失效。有了这些知识，就可以预测治疗和预防遗传性和后天性人类骨骼和关节疾病的新目标。