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 #
5R01HL112641-03
Application #
8589002
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
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$589,694
Indirect Cost
$196,040
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Waghulde, Harshal; Cheng, Xi; Galla, Sarah et al. (2018) Attenuation of Microbiotal Dysbiosis and Hypertension in a CRISPR/Cas9 Gene Ablation Rat Model of GPER1. Hypertension 72:1125-1132
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
Baumgartner, C K; Mattson, J G; Weiler, H et al. (2017) Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost 15:98-109
Kumarasamy, Sivarajan; Solanki, Sumeet; Atolagbe, Oluwatomisin T et al. (2017) Deep Transcriptomic Profiling of M1 Macrophages Lacking Trpc3. Sci Rep 7:39867
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
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
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
Joe, Bina (2015) Dr Lewis Kitchener Dahl, the Dahl rats, and the ""inconvenient truth"" about the genetics of hypertension. Hypertension 65:963-9
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

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