Project 3: Translational Genomics of Hyperuricemia

项目3：高尿酸血症的转化基因组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要慢性肾脏病 (CKD) 与高尿酸血症 (HU) 和痛风密切相关；然而，因果关系关系不清楚。在全基因组关联研究 (GWAS) 中发现的超过 30 个尿酸基因中，有 10 个是也与 CKD 相关。尿酸盐转运蛋白的遗传变异（例如，SLC2A9，编码 GLUT9）转运蛋白）与 HU 和痛风有关；然而，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以及与相关的信号网络的调节作用 HU 和 CKD 对于理解 HU 的功能基因组学及其与 CKD 的因果关系高度相关。此外，APOL1 蛋白与非裔美国人的 CKD 遗传风险相关，与 GLUT9 和我们的数据表明 APOL1 基因型与血清尿酸 (sUA) 存在关联。我们的目标是填补这些空白通过阐明 HU 和 CKD 之间的分子关系来弥补关键知识差距。为了实现这一目标，我们利用尖端的转化生理学提出关键的转化遗传和功能研究和遗传学。在目标 1 中，我们将筛选和表征与这两个相关的调节蛋白（包括 APOL1） HU 和 CKD 以确定与尿酸盐转运的功能相互作用。为了实现这一点，我们将首先检查爪蟾卵母细胞中与 GLUT9 和其他尿酸盐转运蛋白共表达对尿酸盐转运的影响。这该方法已经揭示了双基因 TMEM171/174 基因座的新生理学，具有抑制 TMEM171 影响基底外侧 GLUT9，TMEM174 影响顶端 URAT1 运输。多种重测序资源将筛选这些调控基因中不常见的渗透编码变异，并与极端情况分离在南美航空；然后将表征这些变体的功能效果。在目标 2 中，我们提出了最先进的遗传方法使用非常大的公开数据集来发现因果关系和共享遗传 HU 和 CKD 的病因学。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使用多元贝叶斯全基因组回归 (WGR) 分析 sUA 与 eGFR/CKD 之间的相关性。到确定共同导致 HU 和 eGFR/CKD 的特定基因和途径，我们将估计遗传使用 WGR 确定基因组区域的相关性。我们将研究尿酸升高基因变异的因果作用肾功能下降；这将通过孟德尔随机化进行正式测试。最后，还有一个重大未满足的问题需要一种基因上易于处理的人类尿酸盐稳态模型。我们的研究小组已经证明，人类干细胞衍生的肾细胞自组织成人类肾脏类器官，在功能上重演组织特异性上皮生理学。在目标 3 中，我们将利用该系统研究 CKD 和 HU 相关基因，首先分析 TMEM171/174 基因座中调节性 SNP 的作用以及 TMEM171 和 TMEM174 在肾小管尿酸盐生理学。该项目的完成将为转化尿酸盐研究和研究提供新的工具。对 CKD 和 HU 共享途径的新见解，适合治疗靶向。