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Uncovering sex differences in uric acid handling

揭示尿酸处理的性别差异

基本信息

批准号：
10378012
负责人：
Victoria Halperin Kuhns
金额：
$ 6.98万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378012
关键词：
ABCG2 gene Affect American Animal Model Animals Cardiovascular Diseases Chronic Kidney Failure DNA Binding Data Epithelial Cells Equilibrium ErbB4 gene Estrogens Excretory function Family Feedback Female Financial compensation Foundations Functional disorder Future General Population Genes Genetic Transcription Gonadal Steroid Hormones Gout HNF4A gene Human Hypertension Hyperuricemia IGF1 gene Insulin Kidney Kidney Calculi Kidney Diseases Knock-out Knockout Mice Lead Maps Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Modeling Mus Mutation Nephrons Pathologic Pathway interactions Patients Pattern Phosphorylation Phosphotransferases Physiology Precipitation Premenopause Proto-Oncogene Proteins c-akt Quality of life Regulation Regulatory Pathway Risk Risk Factors Role Serum Sex Differences Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Somatomedins Transactivation Transcriptional Regulation Urate Oxidase Uric Acid Variant Woman comorbidity differential expression disorder risk effective therapy experimental study extracellular female sex hormone genome wide association study hepatocyte nuclear factor human tissue humanized mouse improved in vivo insight kinase inhibitor loss of function mutation male men mouse model novel protective effect renal epithelium risk variant sex transcription factor transcriptome sequencing

项目摘要

Project Summary Hyperuricemia, or elevated serum uric acid, is estimated to effect 20 – 25% of the general population, but only 4 – 6% of pre-menopausal women. Hyperuricemia causes kidney stones and gout, and also is an independent risk factor for chronic kidney disease, cardiovascular disease, hypertension, and metabolic syndrome. Uric acid (UA) excretion is mediated by the kidney (70%) and the gut (30%) and is a complicated balance of reabsorption and secretion. A single nucleotide polymorphism in the gene encoding the primary UA secretory transporter, ABCG2 Q141K, is both a hyperuricemia and gout risk variant, and associates with sex differences in serum uric acid (SUA) levels. The pathophysiology of hyperuricemia and the regulation of ABCG2 and other UA transporters are, however, poorly understood, especially in women. In our recent genome wide association study, we found that two transcription factors, HNF1A and HNF4A, associate with SUA levels and that these transcription factors may directly regulate uric acid transporters like ABCG2. How these transcription factors are influenced by uric acid, and how they may be differentially regulated in women are also unknown. Our preliminary data suggests that UA is acting as a signaling molecule, triggering various kinase cascades that activate transcription of UA transporters. We will explore this hypothesis by first determining if UA levels regulate the important transcription factors HNF1A and HNF4A invitro. Next, we will determine if hyperuricemia regulates transporter transcription factor abundance or activity in our novel hyperuricemia mouse models. Finally, we will explore differential expression of UA transporters in kidneys of male and female mice, and how regulation of these transporters is sex specific. Understanding these mechanisms could lead to better treatment of hyperuricemia to improve patient quality of life and decrease risk of developing associated co- morbidities, such as cardiovascular, metabolic, and kidney diseases.

项目摘要据估计，高尿酸血症或血清尿酸升高会影响20 - 25%的一般人群，但只有4 - 6%的绝经前妇女。高尿酸血症引起肾结石和痛风，也是慢性肾脏疾病的独立危险因素，心血管疾病、高血压和代谢综合征。尿酸（UA）排泄是由肾脏（70%）和肠道（30%）介导，是一个复杂的重吸收平衡和分泌物。编码原发性UA分泌的基因的单核苷酸多态性转运蛋白ABCG 2 Q141 K是一种高尿酸血症和痛风风险变异体，与血清尿酸（SUA）水平的性别差异。高尿酸血症的病理生理学及治疗然而，对ABCG2和其他UA转运蛋白的调控知之甚少，特别是在妇女在我们最近的全基因组关联研究中，我们发现两个转录因子， HNF1A和HNF4A与SUA水平相关，这些转录因子可能直接与SUA水平相关，调节尿酸转运蛋白如ABCG2。这些转录因子如何受到尿酸，以及它们如何在女性中受到不同的调节也是未知的。我们初步数据表明，UA是一种信号分子，触发各种激酶，激活尿酸转运蛋白转录的级联反应。我们将首先探讨这个假设确定UA水平是否在体外调节重要的转录因子HNF 1A和HNF 4A。下一步，我们将确定高尿酸血症是否调节转运蛋白转录因子的丰度，活性在我们的新型高尿酸血症小鼠模型。最后，我们将探讨差异表达雄性和雌性小鼠肾脏中UA转运蛋白的表达，以及这些转运蛋白的调节是性别特异性的了解这些机制可以更好地治疗高尿酸血症，以改善患者的生活质量和降低相关的并发症的风险，疾病，如心血管疾病、代谢疾病和肾脏疾病。