Genome wide association studies (GWAS) have been extremely powerful and successful identifying associations between genetic polymorphisms (SNP) and diabetic and chronic kidney disease (CKD) development. Our next big challenge is to translate this information to understand the mechanism of diabetic and CKD development. The major hurdle is that the majority of CKD associated polymorphisms lie outside the coding region of the genome. Therefore classic protein biochemistry and gene deletion studies of model organisms cannot yet be applied. Several recent pioneering studies have provided a novel framework for such experiments and indicate that the cell type specific epigenome can be used to understand and annotate the non-coding region of the genome. As there are hundreds of established SNPs for CKD, performing individual experiments for each SNP could be a daunting task, therefore there is a critical need for genome wide cell type specific mapping of non-coding regulatory regions and defining the correlation between SNP's and transcript levels. The proposal will use a combination of methods to dissect the association between diabetic and chronic kidney disease associated polymorphisms and disease.

Public Health Relevance

One in ten American -about 20 million people- suffer from chronic kidney disease (CKD). More than half a million people carry the diagnosis of the most severe form of CKD, end stage renal disease (ESRD). ESRD can only be treated with dialysis or transplantation. The yearly mortality rate of patients on dialysis can be as high as 20%, which is higher than patients with prostate or breast cancer. Multiple different approaches have been attempted to understand the mechanism of CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087635-07
Application #
8875669
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rasooly, Rebekah S
Project Start
2009-09-01
Project End
2019-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Qiu, Chengxiang; Huang, Shizheng; Park, Jihwan et al. (2018) Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat Med 24:1721-1731
Zhao, Juanjuan; Lupino, Katherine; Wilkins, Benjamin J et al. (2018) Genomic integration of ERR?-HNF1? regulates renal bioenergetics and prevents chronic kidney disease. Proc Natl Acad Sci U S A 115:E4910-E4919
Li, Szu-Yuan; Susztak, Katalin (2018) The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator 1? (PGC-1?) in Kidney Disease. Semin Nephrol 38:121-126
Sharma, Kumar; Susztak, Katalin; Pennathur, Subramaniam (2018) Introduction: Systems Biology of Kidney Disease. Semin Nephrol 38:99-100
Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763
Beckerman, Pazit; Susztak, Katalin (2018) APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease. Trends Mol Med 24:682-695
Qiu, Chengxiang; Hanson, Robert L; Fufaa, Gudeta et al. (2018) Cytosine methylation predicts renal function decline in American Indians. Kidney Int 93:1417-1431
Ko, Yi-An; Yi, Huiguang; Qiu, Chengxiang et al. (2017) Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease. Am J Hum Genet 100:940-953
Gluck, Caroline; Ko, Yi-An; Susztak, Katalin (2017) Precision Medicine Approaches to Diabetic Kidney Disease: Tissue as an Issue. Curr Diab Rep 17:30
Li, Szu-Yuan; Park, Jihwan; Qiu, Chengxiang et al. (2017) Increasing the level of peroxisome proliferator-activated receptor ? coactivator-1? in podocytes results in collapsing glomerulopathy. JCI Insight 2:

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