Genetic and molecular mechanisms important to the processing of sensory information into abnormal cardiovascular responses remains the focus of this project. We will continue to use the airpuff stress paradigm, which we pioneered for sensori-autonomic processing, as well as restraint and high dietary NaCI stress. Building on our identification of a set of quantitative trait loci (QTL), spread across the genome, which determine cardiovascular and behavioral responses to stressors, we will target specific chromosomal areas to identify candidate genes and potential molecular mechanisms. Our focus remains the SHR model of hypertension using the HXB-BXH set of Recombinant Inbred (RI) rat strains, now rederived into a clean colony in La Jolla, and other strains and congenics. The chromosomal targets of study will be recently identified QTL for (a) the orienting response bradycardia on 2 and 3, (b) airpuff startle elicited tachycardia responses on 1 and 10, and secondarily (c) basal arterial pressure on 8 and airpuff-startle pressor response on 6. We will also study arterial pressor and depressor loci we have identified on 2.
Four aims are identified.
In aim 1 we will develop and test congenics to narrow the target QTL and seek candidate genes. We will use a novel method along with speed congenic strategies.
In aim 2 we will seek to identify candidate genes for the target QTL of Aim 1 by using both specific microarrays and subtractive methods, subtractive suppression hybridization (SSH).
In aim 3, we will directly test the Folkow hypothesis with the thesis that specific genes predispose an organism to hypertension upon repeated environmental stress.
In aim 4 we will seek QTL for borderline hypertension and salt sensitivity in a new, inbred strain, the WKY/ Ij-tf, using segregating populations and genome scanning. We will use a mixed modality repeated stress paradigm applied to specific RI strains, selected for divergent arterial pressure or heart rate responses, and the WKY/ Ij-tf to test for genetic susceptibility. Our efforts will identify new candidate genes responsible for abnormal cardiovascular response to stressors and test if susceptibility to repeated stress is a viable etiological mechanism operative in genetic hypertension of the rat.
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