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.
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