Impact of Alport syndrome mutations and natural interruptions on collagen folding

描述(申请人提供)：该项目将有助于阐明Alport综合征的发病机制，并探索一种新的治疗策略。第一个目标将是研究IV型胶原如何在自然序列中断附近折叠，自然序列中断是正常胶原序列中的良性存在。利用圆二色谱、胰酶敏感性、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类似于导致Alport综合征的甘氨酸错义突变所产生的序列。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，以洞察突变周围的有缺陷的折叠。将使用多肽和重组系统来获得结构和动力学信息。第三个目标是测试小分子伴侣，以确定它们是否可以纠正错义突变造成的折叠缺陷。

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.