Chemistry and Biology of Collagen

胶原蛋白的化学和生物学

• 批准号: 9101491
• 负责人: Ronald T Raines
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101491
• 关键词: Accounting; Affinity; Amides; Amino Acid Sequence; Amino Acids; Animals; Arthritis; Bandage; Beds; Biocompatible Materials; Biological Process; Biology; Carbon; Caring; Cartilage; Catalysis; Cell Surface Receptors; Chemicals; Chemistry; Collagen; Connective Tissue; Data; Disease; Enzymatic Biochemistry; Enzymes; Esters; Extracellular Matrix; Functional disorder; Goals; Grant; Healed; Health; Health Care Costs; Human; Human body; Hydroxylation; Hydroxyproline; Invaded; Knowledge; Link; Methods; Modality; Modeling; Molecular; Molecular Conformation; Mus; Neoplasm Metastasis; Organic Chemistry; Oxygen; Peptides; Post-Translational Protein Processing; Prevalence; Procollagen-Proline Dioxygenase; Proline; Proteins; Reporting; Research; Research Project Grants; Research Proposals; Skin; Structure; Therapeutic Uses; Thioamides; Tissues; Tooth structure; Translating; Vertebral column; Weight; Wound Healing; base; bone; design; fluoro-proline; healing; human disease; in vivo; inhibitor/antagonist; insight; mimetics; molecular assembly/self assembly; nano; novel; polypeptide; polyproline; pre-clinical; synthetic peptide; triple helix; tumor; wound

DESCRIPTION (provided by applicant): Collagen is the most abundant protein in humans, comprising 1/3 of the total protein and 3/4 of the dry weight of skin. Collagen abnormalities are associated with many human diseases, including arthritis. The overall objective of the proposed research is to reveal the chemical basis for the unique triple-helical structure of collagen, and t devise new therapies based on that knowledge. Specific Aims: The four Specific Aims of this research proposal apply methods and ideas from physical organic chemistry, peptide chemistry, molecular self-assembly, chemical enzymology, and matrix biology. Aim 1 is to discern whether enhancing a newly appreciated physicochemical force-the n->?* interaction-can increase triple-helix stability. Aim 2 is to create collagen mimetic peptides that self-assemble into human-scale triple helices that are useful for biomedical applications. Aim 3 is to gain insight into the mechanism of catalysis by human prolyl 4-hydroxylase, which is the enzyme that installs the prevalent and important 4-hydroxyproline residues in collagen strands and is a target for the treatment of fibrotic diseases. Finally, Aim 4 is to use extant knowledge of collagen to create peptide conjugates to assess and heal wounds in mice. Significance: The results of the research proposed herein will provide fundamental insights into the structure and conformational stability of the collagen triple helix, and will use those insights to create transformative molecular therapies for wound care, which now accounts for up to $15B annually in US health care costs, and other indications.

描述（申请人提供）： 胶原蛋白是人体最丰富的蛋白质，占总蛋白质的1/3，占皮肤干重的3/4。胶原蛋白异常与许多人类疾病有关，包括关节炎。拟议研究的总体目标是揭示胶原蛋白独特的三螺旋结构的化学基础，并根据该知识设计新的疗法。具体目标：本研究计划的四个具体目标应用了物理有机化学、肽化学、分子自组装、化学酶学和基质生物学的方法和思想。目标 1 是辨别增强新近认识的物理化学力（n->?* 相互作用）是否可以提高三螺旋稳定性。目标 2 是创建可自组装成可用于生物医学应用的人体规模三螺旋的胶原模拟肽。目标 3 是深入了解人脯氨酰 4-羟化酶的催化机制，这种酶将普遍且重要的 4-羟脯氨酸残基安装在胶原链中，并且是治疗纤维化疾病的靶点。最后，目标 4 是利用现有的胶原蛋白知识来创建肽缀合物来评估和治愈小鼠伤口。意义：本文提出的研究结果将为胶原蛋白三螺旋的结构和构象稳定性提供基本见解，并将利用这些见解来创建用于伤口护理的变革性分子疗法，该疗法目前在美国每年高达 15B 美元医疗保健费用和其他迹象。