Impact of Alport syndrome mutations and natural interruptions on collagen folding

阿尔波特综合征突变和自然中断对胶原蛋白折叠的影响

• 批准号: 7997424
• 负责人: Eileen S Hwang
• 金额: $ 2.94万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997424
• 关键词: Affect; Circular Dichroism; Collagen; Collagen Type IV; Defect; Electron Microscopy; Fluorescence; Glycine; Goals; Hereditary nephritis; Immunosuppressive Agents; Inherited; Interruption; Kidney Diseases; Kidney Failure; Kinetics; Missense Mutation; Molecular Chaperones; Mutation; Pathogenesis; Pharmaceutical Preparations; Predisposition; Recombinants; Research Design; Research Training; Structure; System; Testing; Transplantation; Trypsin; drug testing; improved; insight; prevent; public health relevance; recombinant peptide; small molecule; treatment strategy

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.

描述（由申请人提供）：该项目将有助于阐明Alport综合征的发病机理，并研究一种新的治疗策略。第一个目的是研究IV型胶原蛋白如何围绕自然序列中断折叠，这在正常胶原蛋白序列中存在良性。重组胶原蛋白将用于研究中断对圆形二色性，胰蛋白酶敏感性，荧光和电子显微镜的折叠动力学的影响。自然中断的子集类似于引起促进综合征的甘氨酸错义突变产生的序列。第二个目的是检查这些中断和突变之间的差异，结构和折叠，以洞悉围绕突变的有缺陷的折叠。将采用肽和重组系统来获得结构和动力学信息。第三个目的是测试小分子伴侣，以确定它们是否可以纠正因错义突变引起的折叠缺陷。