ESRD is a major health problem in the United States, with increasing incidence. Hypertension and diabetes account for more than 67% of ESRD. These associations are not understood, but many believe there is a final common pathway for renal failure independent of inducing agent or disease. Not everyone with hypertension or diabetes develops ESRD, and we demonstrated that renal failure genes could be independent of hypertension. We have a comprehensive research program utilizing genetics, genomics, transgenics to study the interactions of hypertension, diabetes and renal disease susceptibility genes. The goal of this proposal is to identify genes responsible for susceptibility to hypertension-related ESRD, and to identify the physiological pathways involved. We propose three specific aims: 1. Validate that Rab38 is the Rf-2 gene. We recently reported Rab38 to be the Rf-2 gene. We hypothesize that the Rab38 gene has pleiotropic effects and contributes to the development of proteinuria in FHH rats. We will test this hypothesis by a) studying albumin uptake in primary cultures of proximal tubule and b) with transgenic """"""""rescue"""""""". 2. Complete the positional cloning and validation of the Rf-1 gene and Rf-4 gene. The Rf-1 QTL isthe dominant locus for ESRD in the FHH. Importantly, this locus has a strong interaction with Rf-4. We have reduced both the Rf-1 interval to 2.5 cM and the Rf-4 interval to 0.8cM, and the entire region has been sequenced in BN rats to a nearly finished level. We will investigate each locus using sub-congenics, physiological studies and sequence comparison to identify the causal gene(s) in both loci. Causal genes will be validated by rat transgenic rescue in the FHH genome background. 3. Initiate the positional cloning of Rf-3. We have demonstrated our ability to clone genes by position. We show that Rf-3 is also in a region linked to renal disease in mouse and human as is the case for Rf-1,-2, and -4. We will use the existing double (Rf-1+3) congenic strain to generate the overlapping congenics in the Rf-3 interval. We are confident that we will either find the gene or narrow down the interval to a handful of genes when we complete the term of this grant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069321-08
Application #
7737374
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
OH, Youngsuk
Project Start
2001-09-30
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
8
Fiscal Year
2010
Total Cost
$378,750
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A et al. (2016) p66Shc regulates renal vascular tone in hypertension-induced nephropathy. J Clin Invest 126:2533-46
Teumer, Alexander; Tin, Adrienne; Sorice, Rossella et al. (2016) Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes. Diabetes 65:803-17
Yeo, Nan Cher; O'Meara, Caitlin C; Bonomo, Jason A et al. (2015) Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. Genome Res 25:57-65
Prisco, Sasha Z; Prokop, Jeremy W; Sarkis, Allison B et al. (2014) Refined mapping of a hypertension susceptibility locus on rat chromosome 12. Hypertension 64:883-90
Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio et al. (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154:691-703
Katter, Katharina; Geurts, Aron M; Hoffmann, Orsolya et al. (2013) Transposon-mediated transgenesis, transgenic rescue, and tissue-specific gene expression in rodents and rabbits. FASEB J 27:930-41
Lazar, Jozef; O'Meara, Caitlin C; Sarkis, Allison B et al. (2013) SORCS1 contributes to the development of renal disease in rats and humans. Physiol Genomics 45:720-8
Rangel-Filho, Artur; Lazar, Jozef; Moreno, Carol et al. (2013) Rab38 modulates proteinuria in model of hypertension-associated renal disease. J Am Soc Nephrol 24:283-92
O'Meara, Caitlin C; Lutz, Michelle M; Sarkis, Allison B et al. (2012) A 4.1-Mb congenic region of Rf-4 contributes to glomerular permeability. J Am Soc Nephrol 23:825-33
O'Meara, Caitlin C; Lazar, Jozef; Hoffman, Matthew et al. (2011) Refined mapping of the renal failure RF-3 quantitative trait locus. J Am Soc Nephrol 22:518-25

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