Mouse Model of X-Linked Alport Syndrome

描述(申请人提供)：Alport综合征是最常见的肾小球遗传性疾病，估计每5000人中就有1人受到影响。大约85%的病例是X连锁的，这是由于编码基底膜IV型胶原C？(IV)链的Col4A5基因突变造成的。目前还没有有效的治疗Alport综合征的方法。患有X连锁疾病的男性会不可避免地发展为终末期肾病。尽管女性携带者的病程通常是良性的，但估计有15%的人会发展为慢性肾功能衰竭。 这项应用的前提是，随着小鼠模型的可用，在理解X连锁Alport综合征作为治疗基础方面的进展将取得不可估量的进展。我们正在产生带有Co14a5点突变的小鼠品系，产生过早停止，并与已知的人类突变相对应。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，我们计划在现有的肾小球毛细血管壁知识的基础上，在我们的模型中调查其生物力学失败的可能性。具体目标是：1)完成Co14a5点突变转基因小鼠的建立；2)表征突变表型的基本结构和功能特征；3)启动突变和对照小鼠肾小球毛细血管稳态的比较。首席研究员是一位成就卓著的分子生物学家和生理学家，主要研究Alport综合征。他加入了明尼苏达大学负责这一领域历史性贡献的研究人员的行列。明尼苏达大学在肾小球生理学和小鼠遗传学领域拥有专业知识的其他合作者将为加强有效治疗基础的拟议努力做出贡献。

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.