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 #
5R01HL020176-37
Application #
8728303
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
2014-06-01
Budget End
2015-05-31
Support Year
37
Fiscal Year
2014
Total Cost
$570,444
Indirect Cost
$193,913
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
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
Singh, Vishal; Chassaing, Benoit; Zhang, Limin et al. (2015) Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. Cell Metab 22:983-96
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
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
Aboualaiwi, Wissam A; Muntean, Brian S; Ratnam, Shobha et al. (2014) Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation. Circulation 129:660-72
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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