Recaptulating transcriptional pathways of human diabetic nephropathy in mice

重现小鼠糖尿病肾病的转录途径

基本信息

批准号：
7907889
负责人：
Frank C Brosius
金额：
$ 32.72万
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 2013-06-30
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）：有效的糖尿病肾病 (DN) 小鼠模型应该复制 DN 患者的分子变化，而不仅仅是病理改变。因此，我们对糖尿病肾病小鼠模型的开发和测试的一般假设是，当前的小鼠模型无法表现出与人类相似的 DN，因为它们无法复制患有进行性 DN 的人类中发生的肾小球和肾小管间质基因表达变化。复制进行性 DN 患者的关键转录组图谱应能在小鼠中诱导进行性 DN。我们使用欧洲肾脏 cDNA 库 (ERCB) 生成的人类 DN 数据对于测试和验证糖尿病并发症动物模型联盟的小鼠模型至关重要。我们使用 ERCB 对人类 DN 进行了初步转录组分析，以确定在人类中但在小鼠模型中没有可靠改变的通路。在人类糖尿病患者的肾小球和肾小管间质中持续改变的一种途径是 JAK/STAT 途径，而在小鼠中则不然。通过实时 PCR 分析证实，所有 JAK 成员的表达均增加。鉴于 JAK2 在介导 DN 相关反应中的关键作用，我们将重点放在 JAK2 上。此外，JAK2 被活性氧激活并与 PPAR( 信号传导相互作用，两者都与 DN 相关。对于我们的 2 个新模型，我们提出足细胞和近端肾小管特异性 Jak2 转基因 db/m C57BLKS 小鼠。对于这些和其他小鼠我们建议联盟中的模型： 1.确定Jak2//db/db BLKS模型和其他AMDCC模型的肾小球和肾小管间质区室中是否再现了人类的转录变化； 2.确定人类DN的所有病理和病理生理特征是否在Jak2//db/db BLKS模型中复制； 3. 确定 JAK2/3 抑制剂是否能阻止 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 DN 的发展； 4.确定ROS的产生是否驱动肾小球和/或肾小管间质室中的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( 激动剂是否可防止肾小球和/或肾小管间质室中的 J.ak2 下游效应。这项研究与糖尿病肾病的研究和预防直接相关，糖尿病肾病是美国肾功能衰竭的主要原因。通过创建和了解发展出类人糖尿病肾病的小鼠模型，我们可以快速进行策略测试，以预防糖尿病肾病。预防和治疗这种疾病。