: The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension and has been a valuable tool for studying the pharmacology and physiology of blood pressure control. However, despite 30 years of research with this model, the primary mechanisms responsible for hypertension in the SHR remain undefined. Recently, we have succeeded in trapping a quantitative trait locus (QTL) for hypertension within a narrow segment of chromosome 8 in a unique congenic strain of SHR. In the current studies, we will exploit this congenic strain together with proven strategies of genome wide expression analysis and meiotic mapping to identify the molecular lesion(s) responsible for the effect of this region of chromosome 8 on blood pressure. We will pursue two alternative hypotheses using complementary strategies as follows: Hypothesis 1. A hypertension gene exists within the target segment of chromosome 8 that is differentially expressed between the SHR and the SHR congenic strain in one of the major organs suspected to be involved in the primary pathogenesis of spontaneous hypertension (brain, adrenal gland, or kidney). Accordingly, we will search for candidates for hypertension within the target chromosome segment by screening for genes that are differentially expressed between these organs of the SHR and the SHR congenic strain and that map back within the congenic segment of chromosome 8. Hypothesis 2. A hypertension gene exists within the target segment of chromosome 8 that is not differentially expressed between the SHR and the SHR congenic strain. To cover for this alternative possibility, we will also narrow the location of the hypertension gene by meiotic mapping analysis of a segregating F2 population derived from the SHR progenitor strain and the SHR congenic strain that carries the target region of chromosome 8 from the BN strain. Hypertension candidate genes will then be isolated using cDNA screening techniques to identify genes expressed in the brain, adrenal gland, or kidney that map within this chromosome region.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056028-07
Application #
6620204
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Barouch, Winifred
Project Start
1997-01-01
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
7
Fiscal Year
2003
Total Cost
$302,000
Indirect Cost
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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; Kajiya, Takashi; Zídek, Václav et al. (2011) Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension 57:731-7
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
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
Johnson, Michelle D; He, Liqun; Herman, Daniel et al. (2009) Dissection of chromosome 18 blood pressure and salt-sensitivity quantitative trait loci in the spontaneously hypertensive rat. Hypertension 54:639-45
Pravenec, M; Kazdova, L; Maxova, M et al. (2008) Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue. Int J Obes (Lond) 32:1848-53
Kurtz, Theodore W; Pravenec, Michal (2008) Molecule-specific effects of angiotensin II-receptor blockers independent of the renin-angiotensin system. Am J Hypertens 21:852-9
Sugimoto, Ken; Kazdova, Ludmila; Qi, Nathan R et al. (2008) Telmisartan increases fatty acid oxidation in skeletal muscle through a peroxisome proliferator-activated receptor-gamma dependent pathway. J Hypertens 26:1209-15

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