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
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
Mehrotra, Aanchal; Joe, Bina; de la Serna, Ivana L (2013) SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension. J Cell Physiol 228:2337-42
Pillai, Resmi; Waghulde, Harshal; Nie, Ying et al. (2013) Isolation and high-throughput sequencing of two closely linked epistatic hypertension susceptibility loci with a panel of bicongenic strains. Physiol Genomics 45:729-36
Kumarasamy, Sivarajan; Gopalakrishnan, Kathirvel; Abdul-Majeed, Shakila et al. (2013) Construction of two novel reciprocal conplastic rat strains and characterization of cardiac mitochondria. Am J Physiol Heart Circ Physiol 304:H22-32