The overall goal of our research is to identify genes as causative biomarkers of 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. Validation of these candidate genes is required for them to be identified as primary susceptibility genes causing hypertension. Such validation studies are typically conducted in mammalian models such as rats or mice. 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 proposal described here seeks to validate the prioritized genetic determinants identified in both rats and humans 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 hypertension research and aligns discovery of candidate genes from human genome-wide association studies. The innovative aspect of the work is that it employs the state-of-the-art targeted gene disruption (knock-out) strategy using zinc-finger nucleases to target three different genes in the three aims proposed. The genes are: A protein-coding gene, A disintegrin-like metalloproteinase with thrombospondin motifs 16 (Adamts16), a transcription factor, Nuclear receptor subfamily 2, group F member 2 (Nr2f2) and Rififylin (Rffl).

Public Health Relevance

Inheritance of hypertension is well documented but the identities of the genes that are inherited and cause hypertension remain largely unknown. Genes that are prioritized through large scale genetic studies in humans have to be validated in suitable animal models. The research proposed seeks to address this issue by applying the newly available targeted gene-disruption platform in rats to validate the causal nature of the genes prioritized through human and rat genetic studies of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112641-01
Application #
8259243
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
OH, Youngsuk
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$690,506
Indirect Cost
$229,554
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
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
Haller, Steven T; Kumarasamy, Sivarajan; Folt, David A et al. (2016) Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney Int :
Mell, Blair; Abdul-Majeed, Shakila; Kumarasamy, Sivarajan et al. (2015) Multiple blood pressure loci with opposing blood pressure effects on rat chromosome 1 in a homologous region linked to hypertension on human chromosome 15. Hypertens Res 38:61-7
Mell, Blair; Jala, Venkatakrishna R; Mathew, Anna V et al. (2015) Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics 47:187-97
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
Baumgartner, C K; Zhang, G; Kuether, E L et al. (2015) Comparison of platelet-derived and plasma factor VIII efficacy using a novel native whole blood thrombin generation assay. J Thromb Haemost 13:2210-9
Kumarasamy, Sivarajan; Waghulde, Harshal; Gopalakrishnan, Kathirvel et al. (2015) Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension. Nat Commun 6:6252
Joe, Bina (2015) Dr Lewis Kitchener Dahl, the Dahl rats, and the "inconvenient truth" about the genetics of hypertension. Hypertension 65:963-9
Abdul-Majeed, Shakila; Mell, Blair; Nauli, Surya M et al. (2014) Cryptorchidism and infertility in rats with targeted disruption of the Adamts16 locus. PLoS One 9:e100967

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