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: 8155328
• 负责人: Eileen S Hwang
• 金额: $ 2.99万
• 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/8155328
• 关键词: Address; Affect; Benchmarking; Biological Models; Chemicals; Circular Dichroism; Clinical Pathology; Collagen; Collagen Type IV; Defect; Electron Microscopy; Fluorescence; Genetic; Glycine; Goals; Health; Hereditary nephritis; Immunosuppressive Agents; In Vitro; Inherited; Interruption; Kidney Diseases; Kidney Failure; Kinetics; Lead; Length; Measures; Missense Mutation; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Mutate; Mutation; Pathogenesis; Pattern; Peptides; Pharmaceutical Preparations; Play; Predisposition; Preventive; Process; Property; Recombinants; Research Design; Research Training; Role; Screening procedure; Structure; System; Techniques; Testing; Transplantation; Trypsin; base; drug testing; high throughput screening; improved; insight; mutant; novel; prevent; protein folding; recombinant peptide; small molecule; treatment strategy; triple helix; wound

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阿尔波特综合征的发病机制并研究新的治疗策略。第一个目标是研究 IV 型胶原蛋白如何围绕自然序列中断折叠，这些中断良性地存在于正常胶原蛋白序列中。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阿尔波特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，以深入了解突变周围的缺陷折叠。将利用肽和重组系统来获取结构和动力学信息。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引起的折叠缺陷。