Recaptulating transcriptional pathways of human diabetic nephropathy in mice

在小鼠中重现人类糖尿病肾病的转录途径

基本信息

批准号：
7151277
负责人：
Frank C Brosius
金额：
$ 28.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Valid murine models of diabetic nephropathy (DN) should replicate the molecular changes and not simply the pathological alterations of patients with DN. Thus, our general hypothesis for development and testing of murine models of diabetic nephropathy is that Current murine models fail to show human-like DN because they fail to replicate glomerular and tubulointerstital gene expression changes that occur in humans with progressive DN. Replication of the critical transcriptomic profiles of patients with progressive DN should induce progressive DN in mice. Our use of data in human DN generated by the European Renal cDNA Bank (ERCB) will be critical in testing and validating the mouse models of the Animal Models of Diabetic Complications Consortium. We have performed initial transcriptomic analyses of humans with DN using the ERCB to identify pathways which are reliably altered in humans but not in murine models. One pathway that is consistently altered in glomeruli and tubulointerstium in diabetes in humans, but not in mice, is the JAK/STAT pathway. Expression of all JAK members was increased when confirmed with real time PCR analysis. We have focused on JAK2 given its key role in mediating responses implicated in DN. Moreover, JAK2 is activated by reactive oxygen species and interacts with PPAR( signaling, both of which are implicated in DN. For our 2 novel models, we propose podocyte and proximal tubular-specific Jak2 transgenic db/m C57BLKS mice. For these and other models in the Consortium we propose to: 1. Determine whether transcriptional changes in humans are reproduced in the glomerular and tubulointersitial compartments of the Jak2//db/db BLKS models, and other AMDCC models; 2. Determine if all the pathologic and pathophysiologic features of human DN are replicated in the Jak2//db/db BLKS models; 3. Determine if JAK2/3 inhibitors prevent development of DN in the Jak2 transgenic models and other good candidate models that replicate human transcriptomic changes; 4. Determine if ROS production drives JAK2 expression in glomerular and/or tubulointerstitial compartments and enhances downstream JAK2 signaling and whether JAK2 expression promotes ROS; 5. Determine if PPAR( agonists prevent J.ak2 downstream effects in glomerular and/or tubulointerstitial compartments. This research is directly relevant to the study and prevention of diabetic kidney disease, the major cause of kidney failure in the U.S. By creating and understanding a mouse model that develops human-like diabetic kidney disease, we can then move rapidly to tests of strategies to prevent and cure this disease.

描述（由申请人提供）：有效的糖尿病性肾病（DN）的鼠模型应复制分子变化，而不仅仅是DN患者的病理改变。因此，我们用于开发和测试糖尿病肾病的鼠模型的一般假设是，当前的鼠模型未能显示出类似人类的DN，因为它们无法复制肾小球和肾小管结构性基因表达的变化，这些基因表达发生了，这些人在具有渐进性DN的人类中发生。进行性DN患者的关键转录组谱的复制应诱导小鼠进行性DN。我们在欧洲肾脏cDNA银行（ERCB）产生的人类DN中使用数据对于测试和验证糖尿病并发症联盟动物模型的小鼠模型至关重要。我们使用ERCB对人类对人类进行了初步转录组分析，以识别人类可靠改变但在鼠模型中没有可靠改变的途径。 JAK/STAT途径是人类糖尿病（但没有小鼠）糖尿病的肾小球和肾小管群中始终改变的一条途径。通过实时PCR分析确认所有JAK成员的表达都会增加。鉴于其在介导与DN有关的反应中的关键作用，我们专注于JAK2。此外，JAK2被活性氧气激活，并与PPAR相互作用（信号传导，这两种含量都与DN有关。对于我们的2个新型模型，我们提出了Podocyte和tobximal管状特异性JAK2转基因DB/M C57BLKS小鼠。 1。确定在JAK2 // DB/DB BLKS模型和其他AMDCC模型的肾小球和肾小管隔室中是否复制人类的转录变化； 2。确定在JAK2 // DB/DB BLKS模型中复制人类DN的所有病理和病理生理特征； 3。确定JAK2/3抑制剂是否可以防止在JAK2转基因模型和其他复制人类转录组变化的良好候选模型中发展DN； 4。确定ROS的产生是否驱动肾小球和/或微管区室中的JAK2表达，并增强下游JAK2信号传导以及JAK2表达是否促进ROS； 5。确定PPAR（激动剂是否可以防止肾小球和/或微管区室中的J.AK2下游效应。这项研究与糖尿病性肾脏疾病的研究和预防直接相关，这是美国肾衰竭的主要原因，是通过创建和理解发展类似人类糖尿病肾脏疾病的小鼠模型，然后我们可以迅速进行预防和治愈这种疾病的策略。