application) The natriuretic peptides represent a family of hormonal, autocrine and paracrine regulators that control cardiovascular homeostasis and fluid balance. They exhibit potent vasodilatory, natriuretic, hypotensive and anti-mitogenic activity in a number of different tissues. They exert these effects through association with high affinity receptors on the surface of target cells and subsequent activation of particulate guanylyl cyclase activity. The latter is encoded at the carboxy terminus of the receptor molecule. The guanylyl cyclase-linked receptors can be separated into two principal forms. The first, NPR-A, binds ANP and BNP with high affinity while NPR-B preferentially associates with CNP. Relatively, little is known about the regulation of these receptors and even less about the expression of their genes. Based on preliminary studies carried out in the investigator's laboratory, as well as other laboratories, it appears that growth status of the target cells, as well as a number of different regulatory factors, control the expression of these genes and the functional activity of their protein products. The focus of the present application will be to dissect the mechanism(s) underlying these regulatory events at the molecular level and to use this information to better understand the physiological or pathophysiological implications of this regulatory activity in the intact animal.
Specific aims will include: (1) to identify the cis-elements and associated trans-acting nuclear proteins which govern basal expression of the NPR genes in target cells. Particular attention will be devoted to the identification of regulatory elements which might account for the differential expression and regulation of the NPR-A vs. NPR-B genes, (2) to elucidate the molecular mechanism(s) underlying the cGMP-dependent regulation of NPR-A promoter activity, (3) to determine the etiology of the increase in NPR-A gene expression in ASMC of the SHR (vs. WKY) rat, (4) to identify the mechanism whereby estrogen activates NPR-A promoter activity, (5) to dissect the mechanism linking extracellular hyperosmolality to elevations in NPR-A gene expression. These studies should provide a clearer picture as to how these receptors are regulated physiologically and how malregulation may contribute to the pathophysiology of cardiovascular and renal disease.
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