Project 3: Translational Genomics of Hyperuricemia

Information

  • Research Project
  • 10263206
  • ApplicationId
    10263206
  • Core Project Number
    P50AR060772
  • Full Project Number
    5P50AR060772-10
  • Serial Number
    060772
  • FOA Number
    RFA-AR-17-001
  • Sub Project Id
    6935
  • Project Start Date
    9/20/2012 - 12 years ago
  • Project End Date
    8/31/2022 - 2 years ago
  • Program Officer Name
  • Budget Start Date
    9/1/2021 - 3 years ago
  • Budget End Date
    8/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    10
  • Suffix
  • Award Notice Date
    9/10/2021 - 3 years ago

Project 3: Translational Genomics of Hyperuricemia

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.

IC Name
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
  • Activity
    P50
  • Administering IC
    AR
  • Application Type
    5
  • Direct Cost Amount
    394375
  • Indirect Cost Amount
    8226
  • Total Cost
  • Sub Project Total Cost
    320282
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NIAMS:320282\
  • Funding Mechanism
    RESEARCH CENTERS
  • Study Section
    ZAR1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    UNIVERSITY OF ALABAMA AT BIRMINGHAM
  • Organization Department
  • Organization DUNS
    063690705
  • Organization City
    BIRMINGHAM
  • Organization State
    AL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    352940001
  • Organization District
    UNITED STATES