Techniques currently exist which permit the introduction of recombinant DNA molecules into the mouse germline, thereby creating """"""""transgenic"""""""" lineages which carry the integrated DNA as a stable, heritable trait. Moreover, the techniques provide a means with which to correlate defined genetic alterations of the integrated """"""""transgene"""""""" with their resultant physiological consequences in intact animals. In this study, the relationship between aberrant Atrial Natriuretic Factor (ANF) expression and hypertension will be investigated. ANF is a peptide hormone produced by the heart which exhibits potent natriuretic and hypotensive properties, and which appears to play a crucial role in the regulation of blood pressure and electrolyte homeostasis. Transgenic lineages will be generated which carry defined alterations of the human ANF gene. Molecular and physiological analyses will be performed on the various lineages to determine the effect of transgene expression on both blood pressure and electrolyte balance. In addition, the physiological response of other components of the blood pressure regulatory cascade will be determined (for example, renin, angiotensin and aldosterone). Initially three experimental tacts will be pursued. They are: 1) experiments which will define the human ANF promoter. 2) experiments which will define the physiological consequences of aberrant ANF regulation due to oncogene expression in atrial pericardiocytes. 3) experiments which will define the physiological consequences of ANF expression directed by heterologous promoters. The proposed experiments will address interesting questions pertaining to the regulation of the ANF gene, as well as provide a model system in which to study the relationship between aberrant ANF expression and hypertension.
