Molecular Mechanisms of Uric Acid Homeostasis

尿酸(UA)是人体嘌呤代谢途径的终末代谢物。尿酸过多，临床上 失调性高尿酸血症，影响4300万美国人，导致痛风，增加高血压、中风的风险， 代谢综合征和慢性肾脏疾病。一种遗传和生理方法导致了我们的身份 多药转运体ABCG2作为高容量尿酸外排转运体和常见的ABCG2变体 对增加尿酸水平和痛风风险有最大的遗传贡献。尽管基因的作用 ABCG2在高尿酸血症和痛风风险中的作用现已得到证实，但我们对其生理作用知之甚少 ABCG2作为一种肾脏尿酸转运蛋白。尿酸的动态平衡过程和饮食一样必然是一个动态的过程 新陈代谢产生高度可变的尿酸负荷。因此，这项提案的首要目标是制定一项 ABCG2介导的肾脏尿酸排泄是如何生理调节的机制解释，以及如何 这一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在体内是生理调节的，是尿酸的关键成分 稳态？2)磷酸化在调节ABCG2和肾脏尿酸排泄中起什么作用？和3) 常见的ABCG2痛风突变Q141K如何改变ABCG2调节和肾脏UA的生理 排泄物？这项工作将对尿酸盐动平衡的分子机制提供新的理解。 阐明调节失调的高尿酸血症对人类健康的影响，以及新的治疗方法 治疗的目标。

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.