INvestigations In Gout, Hyperuricemia, and comorbidiTies (INSIGHT) Center of Research Translation (CORT)

痛风、高尿酸血症和合并症的调查 (INSIGHT) 研究翻译中心 (CORT)

• 批准号: 10175329
• 负责人: Kenneth G Saag
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175329
• 关键词: ABCG2 gene; Acute Renal Failure with Renal Papillary Necrosis; Affect; American; Binding; Cardiovascular Diseases; Cells; Chickens; Chronic Kidney Failure; Code; Data; Data Set; Development; Diabetes Mellitus; Exercise; Familial Hypertrophic Cardiomyopathy; Family; Genes; Glucose Transporter; Gout; Homeostasis; Hyperinsulinism; Hypertrophic Cardiomyopathy; Hyperuricemia; Inflammation Mediators; Inflammatory Arthritis; Insulin; Investigation; Kidney; Laboratories; Link; Loss of Heterozygosity; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular; Multi-Drug Resistance; Nature; Nephrolithiasis; PRKAG2 gene; Pathogenesis; Phosphotransferases; Physiology; Play; Proteins; Regulation; Risk; Role; SLC2A1 gene; Serum; Single Nucleotide Polymorphism; Syndrome; Translational Research; Tubular formation; Urate; Uric Acid; Variant; blood glucose regulation; comorbidity; exome sequencing; genome wide association study; glucose metabolism; insulin sensitivity; loss of function mutation; member; sensor; urate transporter

Project Summary Gout, an inflammatory arthritis, is estimated to affect approximately 10 million Americans. Gout and hyperuricemia, the predisposing metabolic abnormality associated with gout, are associated with several co- morbidities, including chronic kidney disease, diabetes, cardiovascular disease and the metabolic syndrome. Genome-wide association studies (GWAS) have identified >40 genes that influence serum urate concentration (sUA); SLC2A9, encoding the electrogenic urate transporter GLUT9 (glucose transporter 9), was identified as having the highest impact. GLUT9 is the exclusive basolateral exit step in uric acid reabsorption, with bi-allelic loss of function mutations of SLC2A9 leading to hypouricemia with a marked activation of renal urate secretion, nephrolithiasis, and exercise-induced acute kidney injury (“renal hypouricemia”). We suspect that GLUT9 may be regulated by the evolutionary conserved AMP-sensitive kinase (AMPK), and more specifically by PRKAG2, which encodes the ϒ2 subunit. PRKAG2 has been extensively studied with regards to its role in the development of a familial hypertrophic cardiomyopathy syndrome; single nucleotide polymorphisms (SNPs) in PRKAG2 identified in GWAS have also been linked to development of chronic kidney disease, hyperuricemia and increased risk of gout. AMPK, an energy sensor involved in the regulation of glucose metabolism and insulin sensitivity, is a known regulator of members of the GLUT family. The sponsor's laboratory has demonstrated that GLUT9 is the dominant insulin- activated re-absorptive urate transporter, providing a mechanistic explanation for the urate-retaining effects of hyperinsulinemia. We will obtain information on rare coding variants of PRKAG2 from whole exome sequencing and re-sequencing data sets and evaluate their differential effects on the urate transport capacity of GLUT9. Given the interconnected nature between AMPK and the development of several metabolic diseases, we have reason to believe that AMPK plays a pivotal role in the regulation of GLUT9-mediated urate transport, such that these studies will impact considerably on our collective understanding of the molecular physiology of urate homeostasis and the pathogenesis of gout.

项目摘要 痛风是一种炎症性关节炎，估计会影响约1000万美国人。痛风和 高尿酸血症是与痛风相关的易感代谢绝对性，与几个共同血症相关 病毒性，包括慢性肾脏疾病，糖尿病，心血管疾病和代谢综合征。 全基因组关联研究（GWAS）已经鉴定出影响血清尿酸盐浓度的40个基因 （sua）; SLC2A9，编码电源尿酸尿酸转运蛋白glut9（葡萄糖转运蛋白9），被鉴定为 影响最大。 GLUT9是尿酸吸收的独家基底外侧出口步骤 SLC2A9的功能突变丧失导致低核血症，并明显激活肾尿酸盐分泌， 肾结石症和运动诱导的急性肾脏损伤（“肾脏低核血症”）。我们怀疑glut9可能 受进化组成的AMP敏感激酶（AMPK）的调节，更具体地由Prkag2， 编码ϒ2亚基。 PRKAG2在其肥厚型的发展中广泛研究了其在其发展中的作用 心肌病综合征；在GWAS中鉴定的PRKAG2中的单核苷酸多态性（SNP）也已有 我们与慢性肾脏疾病，高毛症和痛风风险增加的发展有关。 ampk，an 参与调节葡萄糖代谢和胰岛素敏感性的能量传感器是已知的调节剂 Glut家族的成员。赞助商的实验室表明，GLUT9是主要的胰岛素 - 激活的重新吸收尿酸盐转运蛋白转运蛋白，为尿酸尿酸盐的保留作用提供了一种机械解释 高胰岛素血症。我们将从整个外显子中获取有关prkag2的稀有编码变体的信息 测序和重新测序数据集并评估其对尿酸酯运输能力的差异影响 glut9。 鉴于AMPK与几种代谢性疾病的发展之间的相互联系，我们有 认为AMPK在GLUT9介导的尿酸盐运输中起关键作用的理由，这样 这些研究将仔细影响我们对尿酸尿酸盐分子生理的集体理解 稳态和痛风的发病机理。