Project 3: Translational Genomics of Hyperuricemia

项目3：高尿酸血症的转化基因组学

• 批准号: 10263206
• 负责人: David Bruce Mount
• 金额: $ 40.26万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263206
• 关键词: APOL1 gene; Affect; African American; Animal Model; Apical; Biochemical; Biological; Biological Models; Chronic Kidney Failure; Code; Complementary DNA; DNA Resequencing; Data; Data Set; Development; Dose; Epithelial Physiology; Etiology; Event; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genomic Segment; Genotype; Goals; Gout; Haplotypes; Homeostasis; Human; Hyperuricemia; Individual; Investigation; Kidney; Kidney Diseases; Knowledge; Link; Measures; Mediating; Mendelian randomization; Minority; Molecular; Organoids; PRKAG2 gene; Pathway interactions; Phosphotransferases; Physiology; Population; Predisposition; Proteins; Records; Regulator Genes; Renal function; Research; Resources; Role; Series; Serum; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; System; Testing; Tissues; Translational Research; Tubular formation; Untranslated RNA; Urate; Uric Acid; Variant; Xenopus oocyte; base; biobank; causal variant; comorbidity; disease phenotype; functional genomics; genetic approach; genetic association; genetic regulatory protein; genetic variant; genome wide association study; genome-wide; high risk; human model; human stem cells; insight; kidney cell; novel; response to injury; therapeutic target; tool; trafficking; trait; translational approach; translational genetics; translational genomics; urate transporter; whole genome

PROJECT SUMMARY Chronic kidney disease (CKD) is strongly associated with hyperuricemia (HU) and gout; however, the causal relationship is unclear. Of >30 urate genes identified in genome-wide association studies (GWAS), ten are also associated with CKD. Genetic variation in urate transporters (e.g., SLC2A9, encoding the GLUT9 transporter) has been implicated in HU and gout; however, exact causal genes and their mechanisms are unclear. The regulatory effects on GLUT9 and other urate transporters and signaling networks associated with HU and CKD are highly relevant to understanding the functional genomics of HU and its causality with CKD. Furthermore, APOL1 protein, linked to the genetic risk of CKD in African Americans, is co-expressed with GLUT9, and our data suggest an association of APOL1 genotype on serum urate (sUA).Our goal is to fill these key knowledge gaps by unraveling the molecular relationship between HU and CKD. To achieve this, we propose key translational genetic and functional studies, using cutting-edge translational physiology and genetics. In Aim 1 we will screen and characterize regulatory proteins (including APOL1) implicated in both HU and CKD to identify functional interactions with urate transport. To accomplish this we will first examine the effects on urate transport in co-expression with GLUT9 and other urate transporters in Xenopus oocytes. This approach has already revealed novel physiology for the digenic TMEM171/174 locus, with inhibition of basolateral GLUT9 by TMEM171 and of apical URAT1 transport by TMEM174. Multiple resequencing resources will be screened for uncommon penetrant coding variants in these regulatory genes, segregating with extremes in sUA; functional effects of these variants will then be characterized. In Aim 2 we propose state-of-the-art genetic approaches using very large, publicly available data sets to discover the causality and shared genetic etiology of HU and CKD. To determine the relative importance of shared genetic and/or environmental contributions to HU and CKD, we will quantify directly the genome-wide marker-based genetic and environmental correlation between sUA and eGFR/CKD using multivariate Bayesian whole genome regression (WGR). To ascertain specific genes and pathways jointly contributing to HU and eGFR/CKD we will estimate the genetic correlation in genomic regions using WGR. We will investigate a causal role of urate-raising genetic variants in reduced renal function; this will be formally tested by Mendelian randomization. Finally, there is a major unmet need for a genetically tractable model of human urate homeostasis. Our group has shown that human stem-cell- derived kidney cells self-organize into human kidney organoids that functionally recapitulate tissue-specific epithelial physiology. In Aim 3 we will utilize this system to study CKD- and HU-associated genes, first analyzing the role of a regulatory SNP in the TMEM171/174 locus and the individual roles of TMEM171 and TMEM174 in renal tubular urate physiology. Completion of the project will yield novel tools for translational urate research and novel insight into shared pathways in CKD and HU, suitable for therapeutic targeting.

项目摘要 慢性肾脏疾病（CKD）与高尿酸血症（HU）和痛风密切相关。但是，因果关系 关系不清楚。在全基因组关联研究（GWAS）中鉴定出> 30个尿酸盐基因，十个是 也与CKD相关。尿素转运蛋白的遗传变异（例如SLC2A9，编码GLUT9 运输者）与Hu和痛风有关；但是，确切的因果基因及其机制是 不清楚。对GLUT9和其他尿酸盐转运蛋白和信号网络的调节作用与 HU和CKD与了解HU的功能基因组及其因果关系高度相关。 此外，APOL1蛋白与非裔美国人CKD的遗传风险有关，与 GLUT9，我们的数据表明APOL1基因型关于血清尿酸含量（SUA）。我们的目标是填充这些 关键知识通过揭开HU和CKD之间的分子关系而差距。为了实现这一目标，我们 提出关键的翻译遗传和功能研究，使用尖端的翻译生理 和遗传学。在AIM 1中，我们将筛选并表征与这两者有关的调节蛋白（包括APOL1） HU和CKD确定与尿酸酯运输的功能相互作用。为了实现这一目标，我们将首先研究 与爪蟾卵母细胞中的GLUT9和其他尿酸盐转运蛋白共表达尿酸盐转运的影响。这 方法已经揭示了Digenic TMEM171/174基因座的新型生理学，并抑制了 TMEM171的基底外侧GLUT9和TMEM174的顶端URAT1转运。多个重新陈述资源 将在这些调节基因中筛选出罕见的渗透编码变体，并以极端分离 在苏阿；然后将表征这些变体的功能效应。在AIM 2中，我们提出了最先进的 使用非常大的公开数据集的遗传方法来发现因果关系并共享遗传 HU和CKD的病因。确定共享遗传和/或环境的相对重要性 对HU和CKD的贡献，我们将直接量化基于全基因组标记的遗传和环境的贡献 使用多元贝叶斯全基因组回归（WGR），SUA和EGFR/CKD之间的相关性。到 确定共同促成HU和EGFR/CKD的特定基因和途径，我们将估计遗传 使用WGR中基因组区域的相关性。我们将研究尿酸盐培养遗传变异的因果作用 肾功能降低；这将通过门德尔随机化正式测试。最后，有一个未满足的 需要人类尿酸盐稳态的遗传学模型。我们的小组表明人类的干细胞 - 衍生的肾细胞会自组织成人类肾脏器官，在功能上概括了组织特异性 上皮生理学。在AIM 3中，我们将使用该系统来研究CKD和HU相关基因，首先分析 调节性SNP在TMEM171/174基因座以及TMEM171和TMEM174在TMEM171/174中的作用 肾小管生理。该项目的完成将产生新颖的工具，用于转化尿酸酯研究和 对CKD和HU中共享途径的新颖洞察力，适合治疗靶向。