SIRT1 Sirtuin in Diabetic Kidney Disease

SIRT1 Sirtuin 在糖尿病肾病中的作用

基本信息

批准号：
9122421
负责人：
Peter Yenlung Chuang
金额：
$ 33.9万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122421
关键词：
Acetylation Adriamycin PFS Affect Apoptosis Applications Grants Autophagocytosis Beryllium Biogenesis Birth Blood Glucose Cell Survival Cells Chronic Data Deacetylase Defect Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Doxycycline End stage renal failure Energy Metabolism Figs - dietary Gene Expression Genetic Genetic Transcription Health Hemodialysis Homeostasis Homologous Gene Human Hyperglycemia In Vitro Individual Injury Injury to Kidney Kidney Kidney Diseases Kidney Transplantation Knockout Mice Lysine MLLT7 gene Mating Types Mitochondria Mitochondrial DNA Modeling Molecular Morbidity - disease rate Morphogenesis Mus Organ Pathogenesis Predisposition Pregnancy Process Proteins Public Health RNA Interference Regulation Renal glomerular disease Resistance Rodent Model Role STAT3 gene Specificity Stress System TP53 gene Testing Tetracyclines Tissues Trans-Activators Tubular formation db/db mouse diabetes management diabetic effective therapy human disease in vivo injured knock-down mesangial cell mortality mouse model non-diabetic novel overexpression p65 podocyte prevent promoter response small hairpin RNA spatiotemporal transcription factor

项目摘要

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.

描述（由申请人提供）：糖尿病肾病是一个重大公共卫生问题，影响着超过 200,000 名患有终末期肾病的美国患者，需要长期血液透析或肾移植来避免显着的发病率和死亡率。即使采用最好的多方面糖尿病管理方法，糖尿病肾病的进展也只能减慢，而不能阻止。为了开发针对这种疾病的更有效的疗法，我们需要更好地了解该疾病的发病机制。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以及患有糖尿病肾病的人类模型中降低，这种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 的减少会使足细胞易于损伤。为了检验我们的假设，我们生成了一种新型小鼠模型，使我们能够以时间和组织特异性可逆地操纵 SIRT1 表达。通过该模型，我们建议通过研究 SIRT1 表达减少的小鼠糖尿病肾病和足细胞损伤的发展来检查 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。我们的结果可以更好地理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够理想的疾病提供新的治疗靶点。