SIRT1 Sirtuin in Diabetic Kidney Disease

描述(申请人提供)：糖尿病肾病是一个主要的公共卫生问题，影响着20多万美国终末期肾病患者，这些患者需要进行慢性血液透析或肾移植，以避免显著的发病率和死亡率。即使采用了最好的多方面糖尿病管理方法，糖尿病肾病的进展也只是减缓了，但并没有停止。为了开发更有效的治疗方法，我们需要对该病的发病机制有更好的了解。我们最近发现，一种名为sirtuin(SIRT1)的蛋白质的表达在糖尿病啮齿动物模型和患有糖尿病肾病的人类中都减少了，这种蛋白质已知可以修改和调节细胞的转录机制。在这里，我们提供了更多的数据来支持SIRT1的减少增加了小鼠对肾脏损伤的易感性。我们假设在糖尿病状态下SIRT1的减少使足细胞容易受到损伤。为了验证我们的假设，我们建立了一个新的小鼠模型，允许我们可逆地操纵具有时间和组织特异性的SIRT1表达。利用这个模型，我们建议通过研究SIRT1表达降低的小鼠糖尿病肾脏疾病的发生和足细胞损伤来检测SIRT1在肾脏足细胞中的功能作用。我们还旨在确定SIRT1降低导致糖尿病肾损害的分子机制。我们的结果可以更好地理解糖尿病足细胞和肾脏损伤的分子机制，并为目前可用的治疗方法不太理想的疾病提供一个新的治疗靶点。

DESCRIPTION (provided by applicant): Diabetic kidney disease is a major public health issue affecting more than 200,000 U.S. individuals with end-stage renal disease, which requires chronic hemodialysis or kidney transplantation to avoid significant morbidity and mortality. Even with the best multi- faceted approach to diabetes management the progression of diabetic nephropathy is only slowed, but not stopped. To develop more effective therapies for this disease we need to have a better understanding of the disease pathogenesis. We recently found that the expression of a protein called sirtuin (SIRT1), which is known to modify and regulate the cell's transcription machinery, is reduced in a rodent model of diabetes as well as human with diabetic nephropathy. Here, we present additional data to support that reduction of SIRT1 increases the susceptibility of mice to kidney injury. We hypothesize that reduction of SIRT1 in the diabetic condition predisposes podocytes to injury. To test our hypothesis we have generated a novel mouse model that allows us to reversibly manipulate SIRT1 expression with both temporal and tissue specificity. With this model we propose to exam the functional role of SIRT1 in the kidney podocyte by studying the development of diabetic kidney disease and podocyte injury in mice with reduced SIRT1 expression. We also aim to identify the molecular mechanism through which SIRT1 reduction causes kidney injury in diabetes. Our results could provide a better understanding of the molecular mechanism of podocyte and kidney injury in diabetes and a novel target of treatment for a disease where currently available therapy is less than optimal.