Novel Mouse Resources for Diabetic Nephropathy

 描述（申请人提供）：糖尿病肾病（DN）是全球慢性肾病（CKD）和终末期肾病（ESRD）的主要病因，也是美国ESRD的最大单一病因，占每年进入透析的患者的近一半，是该国的重大经济负担。但 DN动物模型的数量有限，没有一个能完全重现人类的DN状况。 两种最好的动物DN模型是我们先前产生的BTBR ob/ob小鼠和eNos突变体。我们推测，结合这两种突变体可能会加速DN的进展，并显示出与人类DN患者更相似的表型。DN在BTBR ob/ob小鼠中是唯一逆转的，使得能够研究DN中的足细胞再生。然而，再生足细胞的细胞来源仍然不清楚。 由于负责BTBR背景的基因尚未被鉴定，因此向BTBR ob/ob小鼠添加复合突变需要与BTBR背景进行广泛的回交，花费超过3-4年。在该提案中，我们建议使用新兴的CRISPR技术在BTBR ob/ob背景上快速创建复合突变体。了解DN进展和逆转的分子和细胞机制将为了解成人新足细胞形成是否可能用于包括DN在内的肾脏疾病的再生治疗奠定基础。

 DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the major cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) throughout the world and is the largest single cause of ESRD in the United States, accounting for nearly half of the patients entering dialysis each year, which is a significant financial burden in the country. However, there are only limited numbers of DN animal models, none of which fully recapitulate DN conditions in humans. Two of the best animal DN model are the BTBR ob/ob mouse we generated previously, and eNos mutants. We hypothesized that combining the two mutants may accelerate progression of DN and show more similar phenotypes to human DN patients. DN is reversal uniquely in BTBR ob/ob mice, enabling studies of podocyte regeneration in DN. However, the cellular origin for regenerating podocytes remains unclear. Because genes responsible for BTBR background have not been identified yet, addition of compound mutations to BTBR ob/ob mice requires extensive backcrossing to BTBR background, taking over 3-4 years. In this proposal, we proposed to create compound mutants on the BTBR ob/ob background rapidly using the emerging CRISPR technology. Understanding the molecular and cellular mechanisms for DN progression and reversal would lay the foundation for understanding whether new podocytes formation in adults could be possible for regenerative therapy of kidney diseases including DN.