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
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, Man; Carey, Jacob; Cristiano, Stephen et al. (2017) Genome-Wide Association of Copy Number Polymorphisms and Kidney Function. PLoS One 12:e0170815
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:
Bhagat, Tushar D; Zou, Yiyu; Huang, Shizheng et al. (2017) Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer. J Biol Chem 292:837-846
Beckerman, Pazit; Qiu, Chengxiang; Park, Jihwan et al. (2017) Human Kidney Tubule-Specific Gene Expression Based Dissection of Chronic Kidney Disease Traits. EBioMedicine 24:267-276
Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
Kruse, Michael; Fiallo, Ariana; Tao, Jianling et al. (2017) A High Fat Diet During Pregnancy and Lactation Induces Cardiac and Renal Abnormalities in GLUT4 +/- Male Mice. Kidney Blood Press Res 42:468-482
Chu, Audrey Y; Tin, Adrienne; Schlosser, Pascal et al. (2017) Epigenome-wide association studies identify DNA methylation associated with kidney function. Nat Commun 8:1286
Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142
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

Showing the most recent 10 out of 43 publications