Impact of Alport syndrome mutations and natural interruptions on collagen folding

描述（由申请人提供）：本项目将有助于阐明Alport综合征的发病机制，并研究新的治疗策略。第一个目标将是研究IV型胶原蛋白如何在正常胶原蛋白序列中良性存在的自然序列中断周围折叠。重组胶原蛋白将用于通过圆二色性、胰蛋白酶敏感性、荧光和电子显微镜研究中断对折叠动力学的影响。自然中断的一个子集与导致Alport综合征的甘氨酸错义突变产生的序列相似。第二个目标是检查这些中断和突变在序列，结构和折叠方面的差异，以了解突变周围的缺陷折叠。肽和重组系统将用于获得结构和动力学信息。第三个目标将是测试小分子伴侣，以确定它们是否可以纠正由错义突变引起的折叠缺陷。

DESCRIPTION (provided by applicant): This project will help to clarify the pathogenesis of Alport syndrome and investigate a new strategy for treatment. The first aim will be to study how type IV collagen folds around natural sequence interruptions, which exist benignly in the normal collagen sequence. Recombinant collagen will be used to study the effect of interruptions on folding kinetics by circular dichroism, trypsin susceptibility, fluorescence, and electron microscopy. A subset of natural interruptions is similar to the sequences created by glycine missense mutations that cause Alport syndrome. The second aim will be to examine the differences between these interruptions and mutations in sequence, structure, and folding to provide insight into defective folding around mutations. Peptide and recombinant systems will be employed to obtain structural and kinetic information. The third aim will be to test small molecule chaperones to determine whether they can correct folding defects caused by missense mutations.