Mouse Model of X-Linked Alport Syndrome

X连锁阿尔波特综合征小鼠模型

• 批准号: 6616245
• 负责人: YOAV SEGAL
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616245
• 关键词: Alport syndrome; basement membrane; collagen; disease /disorder model; genetic models; genetically modified animals; laboratory mouse; model design /development; pathologic process; point mutation; renal glomerulus; sex linked trait

DESCRIPTION (provided by applicant): Alport syndrome is the most common genetic disorder of the renal glomerulus, affecting an estimated 1 in 5,000 individuals. Roughly 85% of cases are X-linked, resulting from mutations in the COL4A5 gene, which encodes the c¿(IV) chain of basement membrane type IV collagen. There are currently no effective treatments for Alport syndrome. Males with X-linked disease suffer inexorable progression to end-stage kidney disease. Although female carriers generally have a benign course, an estimated 15% develop chronic renal failure. The premise of this application is that progress towards understanding X-linked Alport syndrome, as grounds for therapy, will be advanced immeasurably by the availability of mouse models. We are generating mouse lines with a Co14a5 point mutation, producing a premature stop, and corresponding to a known human mutation. As X-linked Alport syndrome is an archetypal basement membrane disorder, producing hematuria as a primary manifestation, we plan to build on existing knowledge of the glomerular capillary wall, to investigate the likelihood of its biomechanical failure in our model. Specific Aims are: 1) To complete generation of a transgenic mouse line with a Co14a5 point mutation; 2) To characterize basic structural and functional features of the mutant phenotype; and 3) To initiate comparison of glomerular capillary homeostasis in mutant and control mice.The Principal Investigator is an accomplished molecular biologist and physiologist with primary research interests in Alport syndrome. He joins researchers at the University of Minnesota responsible for historic contributions to this field. Additional collaborators at the University of Minnesota, with expertise in the areas of glomerular physiology and mouse genetics, will contribute to proposed efforts towards strengthening the foundations for effective therapies.

描述（由申请人提供）：Alport综合征是肾小球最常见的遗传性疾病，估计每5，000人中有1人受累。大约85%的病例是X连锁的，由COL 4A 5基因突变引起，该基因编码基底膜IV型胶原蛋白的c？（IV）链。目前还没有有效的治疗Alport综合征。患有X-连锁疾病的男性会不可避免地发展为终末期肾病。虽然女性携带者通常有一个良性的过程，估计15%的发展慢性肾衰竭。 该应用的前提是，小鼠模型的可用性将极大地推动对X连锁Alport综合征（作为治疗依据）的理解取得进展。我们正在产生具有Co 14 a5点突变的小鼠品系，产生过早停止，并对应于已知的人类突变。由于X连锁Alport综合征是一种典型的基底膜疾病，以血尿为主要表现，我们计划建立在肾小球毛细血管壁的现有知识基础上，研究其在我们的模型中生物力学失效的可能性。具体目标是：1）完成具有Co 14 a5点突变的转基因小鼠系的产生; 2）表征突变表型的基本结构和功能特征;和3）开始比较突变小鼠和对照小鼠的肾小球毛细血管稳态。主要研究者是一位有成就的分子生物学家和生理学家，主要研究兴趣是Alport综合征。他加入了明尼苏达大学的研究人员，负责这一领域的历史性贡献。明尼苏达大学的其他合作者，在肾小球生理学和小鼠遗传学领域的专业知识，将有助于加强有效疗法的基础的拟议努力。