The proposed research will continue and extend present investigations into the relationship between the cardiovascular hyperreactivity of the spontaneously hypertensive rat (SHR) to mild alerting stimuli and the etiology of hypertension in this genetic model. Studies are proposed to extend our discovery of a unique, startle-induced heart rate response which identifies a discrete phenotypic difference between SHR and normotensive Wistar-Kyoto (WKY) rats. We have demonstrated that the heart rate trait is inherited in a simple Mendelian fashion and, in the SHR, exhibits genetic linkage to a locus which accounts for over 80% of the hypertension. Further, we have found that the heart rate phenotype involved a central cholinergic pathway which, in response to startle stimuli, activates a parasympathetic response. Studies planned for this grant period will test out thesis that the SHR has a deficient cholinergic activity of this unique, startle-induced pathway. In addition, we seek to define the extent of linkage between the heart rate and hypertension loci, to map these loci using molecular genetics and selected inter-cross breeding between SHR and WKY, to prove or disprove the cholinergic thesis underlying the heart rate phenotype and to identify the brainstem pathways involved. The proposed research identified a totally new direction in efforts to find the hypertension gene(s) in animals an man. In addition, the research proposed should provide new insights into the relationship between environmental stress and cardiovascular disorders, particularly hypertension. Further, the studies directly address the question as to molecular basis of this genetic model of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL035018-10
Application #
5213556
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
1996
Total Cost
Indirect Cost
Harrall, Kylie K; Kechris, Katerina J; Tabakoff, Boris et al. (2016) Uncovering the liver's role in immunity through RNA co-expression networks. Mamm Genome 27:469-84
Saba, Laura M; Flink, Stephen C; Vanderlinden, Lauren A et al. (2015) The sequenced rat brain transcriptome--its use in identifying networks predisposing alcohol consumption. FEBS J 282:3556-78
Vanderlinden, Lauren A; Saba, Laura M; Printz, Morton P et al. (2014) Is the alcohol deprivation effect genetically mediated? Studies with HXB/BXH recombinant inbred rat strains. Alcohol Clin Exp Res 38:2148-57
Pravenec, Michal; Kozich, Viktor; Krijt, Jakub et al. (2013) Folate deficiency is associated with oxidative stress, increased blood pressure, and insulin resistance in spontaneously hypertensive rats. Am J Hypertens 26:135-40
Necká?, Jan; Šilhavy, Jan; Zídek, Václav et al. (2012) CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 44:173-82
Houstek, Josef; Hejzlarova, Katerina; Vrbacky, Marek et al. (2012) Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. Physiol Genomics 44:487-94
Pravenec, Michal; Zidek, Vaclav; Landa, Vladimir et al. (2011) Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 43:372-9
Wikoff, William R; Nagle, Megha A; Kouznetsova, Valentina L et al. (2011) Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J Proteome Res 10:2842-51
Malínská, Hana; Oliyarnyk, Olena; Hubová, Miriam et al. (2010) Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis. Mol Cell Biochem 335:119-25
Rosines, Eran; Johkura, Kohei; Zhang, Xing et al. (2010) Constructing kidney-like tissues from cells based on programs for organ development: toward a method of in vitro tissue engineering of the kidney. Tissue Eng Part A 16:2441-55

Showing the most recent 10 out of 187 publications