The long-term goal of our study is to determine whether certain polymorphic variations in the human genome play causative roles in the common conditions, such as essential hypertension, insulin resistance, abdominal obesity, and atherosclerosis, that are important risk factors for cardiovascular morbidity and mortality. Our working hypothesis is that common variations in the human genome that affect levels of expression of gene products play significant roles in determining risk. While the effect of individual variations may be small, when they are common their impact in the total population can be significant. To model these forms of quantitative variation, we propose to develop a new systematic procedure enabling the levels of gene expression to be altered at will in mice. The procedure depends upon targeted modification of 3'untranslated region (UTR) sequences of genes to generate mice with low (or high) expression of a gene in the whole body yet with the ability to increase (or decrease) the expression level in specific tissues. Expression will be altered from """"""""low"""""""" to """"""""high"""""""", or vice versa, in whole body or in tissue-specific fashion when mice are mated to an animal carrying a Cre-recombinase gene. We propose here to apply this new procedure to the genes coding for angiotensin II type 1 receptor (Agtr1a) and cytochrome P450 3A11 (Cyp3a11), which are respectively a well-established and a new candidate gene for essential hypertension. We will use blood pressure and body fat mass and distribution of resulting mice as the two primary quantitative endpoints. We expect that our new method will facilitate testing whether other inherited quantitative variants in the human genome have causative effects on complex diseases, a highly important problem in relation to human welfare. The """"""""low-high"""""""" strains of mice that we produce should aid in distinguishing between local and systemic effects of gene expression and allow further dissection of the underlying molecular mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077145-05
Application #
7589699
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$344,378
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Liu, Ya-Hui; Tsai, Yau-Sheng; Lin, Shih-Chieh et al. (2016) Quantitative PPAR? expression affects the balance between tolerance and immunity. Sci Rep 6:26646
Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming et al. (2014) Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice. Am J Pathol 184:442-53
James, Leighton R; Le, Catherine; Doherty, Heather et al. (2013) Connective tissue growth factor (CTGF) expression modulates response to high glucose. PLoS One 8:e70441
Li, Feng; Hagaman, John R; Kim, Hyung-Suk et al. (2012) eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype. J Am Soc Nephrol 23:652-60
Johnson, Lance A; Arbones-Mainar, Jose M; Fox, Raymond G et al. (2011) Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor. Diabetes 60:2285-94
Keen, Henry L; Halabi, Carmen M; Beyer, Andreas M et al. (2010) Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta. Arterioscler Thromb Vasc Biol 30:518-25
Doherty, Heather E; Kim, Hyung-Suk; Hiller, Sylvia et al. (2010) A mouse strain where basal connective tissue growth factor gene expression can be switched from low to high. PLoS One 5:e12909
Kandalam, Vijay; Basu, Ratnadeep; Abraham, Thomas et al. (2010) Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction. Am J Physiol Heart Circ Physiol 299:H1012-23
Pendse, Avani A; Johnson, Lance A; Tsai, Yau-Sheng et al. (2010) Pparg-P465L mutation worsens hyperglycemia in Ins2-Akita female mice via adipose-specific insulin resistance and storage dysfunction. Diabetes 59:2890-7
Pendse, Avani A; Arbones-Mainar, Jose M; Johnson, Lance A et al. (2009) Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond. J Lipid Res 50 Suppl:S178-82

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