The objective of this renewal application is to continue work begun during the prior funding period focused on the analysis of the role of various candidate genes in hypertension through the manipulation of their dosage in genetically engineered mice. This prior work involved using gene targeting to create mice with zero, one, two, three, and four copies of candidate genes targeted at their normal chromosomal locations and then assessing the impact of these defined alterations on hypertension in the mouse. The studies demonstrated that gene dosage determines the levels of expression of these genes which either directly impacted on blood pressure, or had blunted effects on blood pressure due to homeostatic adjustments mediated by other genetic elements. The hypothesis that was developed from these prior studies and which is to be tested in the proposed studies are that variations in the level of expression of a variety of genes will lead to blood pressure changes that may be a reflection of increased expression of the manipulated genes or may be blunted or completely missed depending on the homeostatic adjustments mediated by other elements. Dr. Smithies interprets these blunted changes as virtual blood pressure changes since homeostatic adjustments (i.e.) altered chronic expression by other non-manipulated genes sensing blood pressure changes) which can be demonstrated result in an absence of detectable blood pressure changes. This hypothesis and its implications for the genetics of hypertension will be tested by the applicant in five specific aims. The first four aims will investigate the effects on blood pressure of altered expression of f our candidate genes: 1) the renin 1C gene 2) the Agtr1A gene 3) the type A natriuretic peptide receptor gene 4) the natriuretic peptide "clearance" type receptor gene. The final specific aim involves the development of a path diagram displaying the interaction of these genetic determinants from Aims 1-4. This includes predictions and the testing of these predictions using crosses between the mice generated for these studies.