SIRT1 Sirtuin in Diabetic Kidney Disease

描述（由申请人提供）：糖尿病肾病是一个主要的公共卫生问题，影响超过200，000名美国终末期肾病患者，需要长期血液透析或肾移植以避免显著的发病率和死亡率。即使是最好的多方面的糖尿病管理方法，糖尿病肾病的进展也只是减缓，而不是停止。为了开发更有效的治疗方法，我们需要更好地了解疾病的发病机制。我们最近发现，一种称为sirtuin（SIRT1）的蛋白质的表达在啮齿动物糖尿病模型和糖尿病肾病患者中减少，该蛋白质已知可以修饰和调节细胞的转录机制。在这里，我们提供了额外的数据来支持SIRT1的减少增加了小鼠对肾损伤的易感性。我们假设SIRT1在糖尿病状态下的减少使足细胞易于损伤。为了验证我们的假设，我们已经产生了一种新的小鼠模型，使我们能够可逆地操纵SIRT1的表达与时间和组织特异性。在此模型中，我们提出通过研究SIRT1表达降低的小鼠糖尿病肾病和足细胞损伤的发展来检查SIRT1在肾脏足细胞中的功能作用。我们还旨在确定SIRT1减少导致糖尿病肾损伤的分子机制。我们的研究结果可以更好地了解糖尿病足细胞和肾损伤的分子机制，并为目前可用的治疗方法不理想的疾病提供新的治疗靶点。

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.