Chemistry and Biology of Collagen

描述（由申请人提供）：胶原蛋白是人类最丰富的蛋白质，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。这项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，并在此基础上设计新的治疗方法。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。目的1是辨别增强一种新认识到的物理化学力——n->？*相互作用-可以增加三螺旋稳定性。目标2是创造胶原模拟肽，自组装成人体尺度的三螺旋，对生物医学应用有用。目的3是深入了解人类脯氨酸4-羟化酶的催化机制，该酶是在胶原链中安装普遍和重要的4-羟基脯氨酸残基的酶，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造肽偶联物，以评估和愈合小鼠的伤口。意义：本文提出的研究结果将为胶原蛋白三螺旋结构和构象稳定性提供基本见解，并将利用这些见解创建用于伤口护理的变革性分子疗法，目前伤口护理每年在美国医疗保健费用中高达150亿美元，以及其他适应症。

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.