The overall goal of our research is to identify genetic elements causing hypertension. Over 90% of all hypertension develops for no known reasons. This form, called as essential hypertension, is a serious risk factor and predictor of future cardiovascular, renal diseases and/or stroke. Although genetics is known to be responsible for up to 30% of the incidence of essential hypertension, the genes conferring susceptibility to develop hypertension have been only prioritized as candidate genes in both humans and in animal models. Using rat genetic models of hypertension we have mapped several regions of the rat genome as those that contain genetic determinants of blood pressure. The important aspect of these studies is that they are quite advanced in the sense that the resolutions of mapped locations are within mega- or kilobase segments. We propose to continue these high resolution mapping studies, prioritize candidate variants and validate the prioritized genetic determinants identified in rats as candidate genetic determinants of blood pressure. The significance of this work is that it is based on systematic and sustained genetic mapping studies in rats to the best resolutions known in the field of experimental hypertension research and aligns discovery of candidate genes from human genome-wide association studies.
Four aims are proposed, each of which is focused on blood pressure quantitative trait loci on different rat chromosomes (chromosomes 1, 9, 10 and 5). The innovative aspect of the work is that it employs the state-of-the-art targeted gene disruption (knock-out) and knock-in rescue strategies using zinc-finger nucleases to further validate the prioritized genetic elements, which in at least one case, is potentially a noncoding RNA.

Public Health Relevance

Identifying genetic factors contributing to inheritance of hypertension in humans is difficult give that such factors account for only ~30% whereas the remainder larger component is the highly variable environmental factors. Using unique rat genetic models of hypertension that we have developed, we have identified many regions of the rat genome as those containing blood pressure regulatory genes and prioritized the evaluation of novel genetic elements. The proposal seeks to continue these studies and validate the underlying genetic elements.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL020176-36
Application #
8546560
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (02))
Program Officer
OH, Youngsuk
Project Start
1988-06-01
Project End
2018-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
36
Fiscal Year
2013
Total Cost
$554,148
Indirect Cost
$188,374
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Haller, Steven T; Kumarasamy, Sivarajan; Folt, David A et al. (2017) Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney Int 91:365-374
Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T et al. (2017) Deep Transcriptomic Profiling of M1 Macrophages Lacking Trpc3. Sci Rep 7:39867
Yeoh, Beng San; Aguilera Olvera, Rodrigo; Singh, Vishal et al. (2016) Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter-Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. Am J Pathol 186:912-26
Yeoh, Beng San; Saha, Piu; Singh, Vishal et al. (2016) Deficiency of stearoyl-CoA desaturase-1 aggravates colitogenic potential of adoptively transferred effector T cells. Am J Physiol Gastrointest Liver Physiol 311:G713-G723
Nie, Ying; Kumarasamy, Sivarajan; Waghulde, Harshal et al. (2016) High-resolution mapping of a novel rat blood pressure locus on chromosome 9 to a region containing the Spp2 gene and colocalization of a QTL for bone mass. Physiol Genomics 48:409-19
Oh, Young S; Appel, Lawrence J; Galis, Zorina S et al. (2016) National Heart, Lung, and Blood Institute Working Group Report on Salt in Human Health and Sickness: Building on the Current Scientific Evidence. Hypertension 68:281-8
Cheng, Xi; Waghulde, Harshal; Mell, Blair et al. (2016) Pleiotropic Effect of a High Resolution Mapped Blood Pressure QTL on Tumorigenesis. PLoS One 11:e0153519
Bai, Yan; Wu, Jian; Li, Daxiang et al. (2016) Differential roles of caveolin-1 in ouabain-induced Na+/K+-ATPase cardiac signaling and contractility. Physiol Genomics 48:739-748
Gopalakrishnan, Kathirvel; Kumarasamy, Sivarajan; Mell, Blair et al. (2015) Genome-wide identification of long noncoding RNAs in rat models of cardiovascular and renal disease. Hypertension 65:200-10
Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian et al. (2015) MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J Mol Cell Cardiol 88:101-10

Showing the most recent 10 out of 63 publications