Salt sensitivity of blood pressure (BP) is a substantial risk factor for cardiovascular (CV) morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension (HTN) and salt sensitive BP (SSBP). Key homeostatic mechanisms that regulate renal sodium reabsorption are: 1) hormonal, e.g., renin-angiotensin-aldosterone (ALDO) system (RAAS) and 2) vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to HTN and SSBP. We recently documented that striatin (STRN) plays a novel role in the development of SSBP. However, the mechanisms that lead to STRN-mediated SSBP are not clear; defining these mechanisms is the overall goal of this proposal. Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to steroids’ mechanism of action. In a large cohort of well characterized subjects, we documented that hypertensive and normotensive humans who are STRN risk allele carriers have SSBP. We then developed a STRN heterozygous knockout (HET-KO) as a tool to identify potential mechanisms for the SSBP. We documented that HET-KO mice also have SSBP with higher BP levels and inappropriately increased ALDO levels on a liberal salt diet. Thus, our overall hypotheses are that STRN deficiency causes increased BP on a liberal salt diet and SSBP by impairing normal sodium excretion in response to a liberal salt intake. At least two mechanisms are likely involved –1) impaired vasorelaxation, particularly of the renal vasculature, and 2) dysfunctional ALDO secretion and action. Using a translational approach, we will test our overall hypotheses by addressing the following Aims: 1) Hypothesis: Human hypertensive STRN risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine); 2) Hypothesis: STRN deficiency leads to excess aldosterone secretion in response to a liberal salt diet because of primary zona glomerulosa dysfunction(s); and 3) Hypothesis: STRN deficiency impairs the normal increase in renal blood flow associated with a liberal salt intake, thereby, leading to sodium retention, volume expansion and an increase in blood pressure. Completion of these Aims will improve our understanding of how STRN interacts with two major sodium/volume homeostatic systems when salt intake changes –ALDO secretion and renal vasodilation– and that reduction in STRN levels causes inappropriate sodium retention resulting in SSBP and increased risk of HTN. Thus, these studies will provide entrée to valuable novel approaches to specifically prevent and/or treat HTN and CV disease--- personalized medicine.