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Molecular Mechanisms of Uric Acid Homeostasis

尿酸稳态的分子机制

基本信息

批准号：
9925221
负责人：
OWEN M WOODWARD
金额：
$ 34.76万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925221
关键词：
ABCG2 gene ATP Hydrolysis Address Affect American Animal Model Binding Biological Cells Chronic Kidney Failure Clinical Defect Diet Disease Disease model Etiology Excretory function Functional disorder Genetic Genetic Diseases Goals Gout Gout Suppressants Health Homeostasis Human Hypertension Hyperuricemia In Vitro Increased Uric Acid Level Individual Kidney Knock-in Mouse Mediating Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Modeling Molecular Mus Mutation Nucleotides Pathogenicity Pathway interactions Patients Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Post-Translational Regulation Process Proteins Purines Reactive Oxygen Species Regulation Risk Risk Factors Role Serum Stroke Structure Testing Therapeutic Time Translating Urate Urate Oxidase Uric Acid Variant Work base drug development extracellular genetic approach human disease in vivo interdisciplinary approach mouse model multi drug transporter mutant new therapeutic target renal epithelium spelling trafficking

项目摘要

Uric acid (UA) is a terminal metabolite of the purine metabolic pathway in humans. Excess UA, the clinical disorder hyperuricemia, affects 43 million Americans causing gout and increasing risk for hypertension, stroke, metabolic syndrome, and chronic kidney disease. A genetic and physiological approach led to our identification of the multidrug transporter ABCG2 as a high capacity UA efflux transporter and that common ABCG2 variants make the largest genetic contribution to increased UA levels and gout risk. Although the genetic role of ABCG2 in hyperuricemia and gout risk is now well established, we know little of the physiological role of ABCG2 as a renal UA transporter. The process of UA homeostasis is by necessity a dynamic process as diet and metabolism produce highly variable UA loads. Thus, the overarching goal of this proposal is to develop a mechanistic explanation of how ABCG2 mediated renal UA excretion is physiologically regulated, and how dysfunction of the process leads to hyperuricemia and human disease. The AIMs of our proposal will address the following three questions: 1) Is ABCG2 physiologically regulated in vivo and a critical component of UA homeostasis? 2) What role does phosphorylation play in regulating ABCG2 and renal UA excretion? and 3) How does the common ABCG2 gout mutation Q141K alter ABCG2 regulation and the physiology of renal UA excretion? This work will provide a new understanding of the molecular mechanisms of urate homeostasis and illuminate both the consequences of dysregulated hyperuricemia on human health, and novel therapeutic targets for treatment.

尿酸（UA）是人体嘌呤代谢途径的终末代谢产物。过量UA，临床高尿酸血症影响了 4300 万美国人，导致痛风并增加高血压、中风、代谢综合征和慢性肾脏病。遗传和生理学方法导致我们的鉴定多药转运蛋白 ABCG2 作为高容量 UA 外排转运蛋白以及常见的 ABCG2 变体对尿酸水平和痛风风险增加的遗传贡献最大。虽然遗传作用 ABCG2 在高尿酸血症和痛风风险中的作用现已得到充分证实，但我们对其生理作用知之甚少 ABCG2 作为肾脏 UA 转运蛋白。 UA 稳态的过程必然是一个动态过程，就像饮食一样和新陈代谢产生高度可变的尿酸负荷。因此，本提案的总体目标是制定一个 ABCG2 介导的肾脏 UA 排泄如何进行生理调节的机制解释，以及如何该过程的功能障碍会导致高尿酸血症和人类疾病。我们提案的目标将解决以下三个问题：1）ABCG2是否在体内受到生理调节并且是UA的关键组成部分体内平衡？ 2）磷酸化在调节ABCG2和肾UA排泄中起什么作用？和 3) 常见的 ABCG2 痛风突变 Q141K 如何改变 ABCG2 调节和肾 UA 的生理学排泄？这项工作将为尿酸稳态的分子机制和阐明高尿酸血症失调对人类健康的影响以及新的治疗方法治疗目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of body mass index on serum urate and renal uric acid handling responses to an oral inosine load: experimental intervention study in healthy volunteers.

DOI：
10.1186/s13075-020-02357-y
发表时间：
2020-11-04
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
Dalbeth N;Allan J;Gamble GD;Horne A;Woodward OM;Stamp LK;Merriman TR
通讯作者：
Merriman TR

Urate transport in health and disease.

DOI：
10.1016/j.berh.2021.101717
发表时间：
2021-12
期刊：
Best practice & research. Clinical rheumatology
影响因子：
0
作者：
Halperin Kuhns VL;Woodward OM
通讯作者：
Woodward OM

Renal Transcriptional Profiles of Hyperuricemic Mouse Models Reveal Urate Dependent Alternations in Metabolic Pathways.

高尿酸血症小鼠模型的肾脏转录谱揭示了代谢途径中尿酸依赖性的改变。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
HalperinKuhns,VictoriaL;Lane-Harris,AllisonC;Woodward,OwenM
通讯作者：
Woodward,OwenM

Slc2a5 (GLUT5) upregulation in hyperuricemia drives risk for fructose induced NAFLD.

高尿酸血症中 Slc2a5 (GLUT5) 的上调会增加果糖诱发 NAFLD 的风险。