SIRT1 Sirtuin in Diabetic Kidney Disease

描述（由申请人提供）：糖尿病肾病是影响20多万美国终末期肾病患者的主要公共卫生问题，需要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这种疾病的发病机制。我们最近发现，一种被称为sirtuin （SIRT1）的蛋白质的表达在糖尿病啮齿动物模型和糖尿病肾病患者中减少，SIRT1被认为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的减少会增加小鼠对肾损伤的易感性。我们假设，糖尿病患者SIRT1的减少使足细胞容易受伤。为了验证我们的假设，我们建立了一种新的小鼠模型，使我们能够以时间和组织特异性可逆地操纵SIRT1表达。在这个模型中，我们提出通过研究SIRT1表达降低的小鼠糖尿病肾病的发展和足细胞损伤来检验SIRT1在肾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理解糖尿病足细胞和肾脏损伤的分子机制，并为目前可用治疗方法不太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.