Left ventricular hypertrophy (LVH) with heart failure and arteriolopathy of renal vessels are cardinal manifestations of target organ damage in chronic hypertension. We hypothesize that genes predisposing to target organ damage in hypertension operate independently of blood pressure. To identify genetic factors that predispose to target organ damage, we will take advantage of transgenic mouse models that develop LVH and nephrosclerosis with striking similarities to the pathology of human hypertension, but in the absence of elevated blood pressure. We propose the following specific aims: (1) To identify modifier genes that accelerates the severity of LVH and heart failure in a transgenic mouse model. The calsequestrin (CSQ) transgenic mouse model recapitulates many of the features of hypertensive cardiomyopathy. Our preliminary studies have identified a strong modifier locus conferring reduced survival that we have linked to a narrow region on mouse chromosome 2. (2) To identify modifier genes a transgenic mouse model of heart failure that prolong survival without improving cardiac function. In preliminary experiments, backcrossing of the CSQ transgene onto a """"""""resistant"""""""" background produces a broad prolongation of survival. (3) To identify modifier genes that confer susceptibility to nephrosclerosis in angiotensin receptor-deficient mice. We have identified strong genetic modifiers that predispose angiotensin receptor-deficient mice to develop a severe renal phenotype resembling hypertensive nephrosclerosis in humans, yet they in the absence of hypertension. Preliminary analysis shows phenotypic segregation suggesting susceptibility to two recessive loci with strong modifying effects. Genomic micro-satellite analysis will be used to map the disease modifying loci and minimal candidate regions. Modifying genes will then be identified using standard positional cloning techniques. Finally, we will test whether the sequence polymorphisms contained within these loci alter susceptibility to target organ injury. The scope of this proposal provides a unique opportunity to develop this program as a unit to maximize efficiency and sharing of resources, taking full advantage of the complementing expertise of the investigative group. Our long-term goal is to identify genes that confer susceptibility to heart and kidney injury in hypertension.
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