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.

项目摘要高尿酸血症或血清尿酸升高，估计有20 - 25％普通人群，但只有4 - 6％的绝经前妇女。高尿酸血症会引起肾脏石头和痛风，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％）和肠道介导（30％），是复杂的重新吸附平衡和分泌。编码主要UA分泌的基因中的单个核丁基多态性转运蛋白ABCG2 Q141K既是高尿酸含量和痛风风险变体，又是与血清尿酸（SUA）水平的性别差异。高核血症的病理生理学和但是，对ABCG2和其他UA转运蛋白的调节是不了解的，尤其是在女性。在我们最近的基因组广泛关联研究中，我们发现两个转录因子，分别 HNF1A和HNF4A，与SUA级别相关，这些转录因子可能直接调节尿酸转运蛋白等ABCG2。这些转录因子如何受到尿酸，以及在女性中如何有所不同的调节也未知。我们的初步数据表明UA充当信号分子，触发各种激酶激活UA转运蛋白转录的级联反应。我们将首先探讨这一假设确定UA水平是否调节重要的转录因子HNF1A和HNF4A Invitro。接下来，我们将确定高纤维症是否调节转运蛋白转录因子滥用或在我们新颖的高尿症小鼠模型中的活性。最后，我们将探索差异表达雄性和雌性小鼠肾脏中的UA转运蛋白，以及这些转运蛋白的调节是特定的。了解这些机制可能会更好地治疗高尿毒血症以提高患者的生活质量并降低发展相关共同的风险病态，例如心血管，代谢和肾脏疾病。