The goal of this PPG is to advance our understanding ofthe complex regulation and interplay of a set of genes residing in two different regions of chr 13 but which together are responsible, in large measure, for salt-induced hypertension, renal injury, and vascularity/angiogenesis of the microcirculation in the saltsensitive (SS) rat. The studies are collectively designed to explore how genetic polymorphisms are translated into integrated cellular, tissue, organ and whole animal function. Project 1 hypothesizes that sequence variants of one or more ofthe genes within a congenic region of chr 13 alter molecular regulatory networks affecting function of the medullary thick ascending limb (mTAL) of SS rats and contribute to the development of salt-sensitive hypertension and renal injury. This will tested by: 1) generating finished-level genomic sequence with complete annotation of this congenic region;2) by constructing a molecular and physiological regulatory network of the mTAL epithelial cell and identifying pathways and genes that may contribute to hypertension and renal injury;and 3) by studying the impact of removing or overexpressing an important gene in the transcriptome/proteome/metabolome associated network. Project 2 will examine a novel hypothesis that non-protein-coding genes may play important roles in hypertension and related tissue injury. We hypothesize that miR-214 contributes to the development of salt-sensitive hypertension and renal injury and examine: 1) the functional contribution of the microRNA within the kidney;2) examine downstream mechanisms mediating its effects, examine upstream trans and cis mechanisms;and 3) carry out a pilot study of miR-214 in human salt-sensitive hypertension and renal injury. Project 3 hypothesizes that a mutation(s) in the SS rat is responsible forthe impaired angiogenesis in this model. We will: 1) identify sequence variants;2) demonstrate that these variants impact renin regulation in vitro;and 3) using a transgenic approach, demonstrate that the SS allele is capable of eliminating normal renin regulation and the angiogenic phenotype in vivo. The collaborative research of this PPG will be supported by Administrative Core A, Genomic and Transgenic Core B, and the Research Services Core C.

Public Health Relevance

More than 50 million Americans have essential hypertension with salt-sensitivity a prominent feature in certain populations of hypertensive patients such as African Americans who also exhibit significantly higher risk of end organ renal damage. This grant will explore the genetic and physiological basis of this form of hypertension to reveal new therapeutic targets for the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL082798-08
Application #
8486467
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
2006-02-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$2,160,350
Indirect Cost
$728,271
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Dayton, Alex; Exner, Eric C; Bukowy, John D et al. (2016) Breaking the Cycle: Estrous Variation Does Not Require Increased Sample Size in the Study of Female Rats. Hypertension 68:1139-1144
Pavlov, Tengis S; Levchenko, Vladislav; Ilatovskaya, Daria V et al. (2016) Renal sodium transport in renin-deficient Dahl salt-sensitive rats. J Renin Angiotensin Aldosterone Syst 17:
Kotchen, Theodore A; Cowley Jr, Allen W; Liang, Mingyu (2016) Ushering Hypertension Into a New Era of Precision Medicine. JAMA 315:343-4
Cowley Jr, Allen W; Yang, Chun; Kumar, Vikash et al. (2016) Pappa2 is linked to salt-sensitive hypertension in Dahl S rats. Physiol Genomics 48:62-72
Prisco, Anthony R; Hoffmann, Brian R; Kaczorowski, Catherine C et al. (2016) Tumor Necrosis Factor α Regulates Endothelial Progenitor Cell Migration via CADM1 and NF-kB. Stem Cells 34:1922-33
Peterson, Christine B; Stingo, Francesco C; Vannucci, Marina (2016) Joint Bayesian variable and graph selection for regression models with network-structured predictors. Stat Med 35:1017-31
Huang, Baorui; Cheng, Yuan; Usa, Kristie et al. (2016) Renal Tumor Necrosis Factor α Contributes to Hypertension in Dahl Salt-Sensitive Rats. Sci Rep 6:21960
Geurts, Aron M; Mattson, David L; Liu, Pengyuan et al. (2015) Maternal diet during gestation and lactation modifies the severity of salt-induced hypertension and renal injury in Dahl salt-sensitive rats. Hypertension 65:447-55
Salehpour, F; Ghanian, Z; Yang, C et al. (2015) Effects of p67phox on the mitochondrial oxidative state in the kidney of Dahl salt-sensitive rats: optical fluorescence 3-D cryoimaging. Am J Physiol Renal Physiol 309:F377-82
Prisco, Anthony R; Prisco, Michael R; Carlson, Brian E et al. (2015) TNF-α increases endothelial progenitor cell adhesion to the endothelium by increasing bond expression and affinity. Am J Physiol Heart Circ Physiol 308:H1368-81

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