A major long-term goal of this Program Project Grant (PPG) has been to develop a quantitative systems analysis of cardiovascular (CV) dynamics and related control systems, including the kidneys, the sympathetic nervous system (SNS), endothelial factors, and the endocrine system. Our experimental studies have focused on understanding the basic molecular and physiological control mechanisms of each component of the circulation, the feedback systems that coordinate these components, and integration of this information into a composite systems analysis of CV regulation. Another key objective has been to translate our research on basic mechanisms of CV control to understanding the pathophysiology of disorders such as hypertension (HT). The current focus of the PPG is on neurohumoral, endothelial, and intrarenal mechanisms that contribute to impaired pressure natriuresis and increased blood pressure (BP) in experimental models that are highly relevant to common, and difficult to treat, forms of human HT caused by obesity, preeclampsia, and postmenopausal hyperandrogenemia. Four unique features of this program are: 1) it utilizes an integrative approach to understand complex interactions between multiple components of CV control systems;2) it focuses mainly on long-term control of the circulation because many CV diseases, such as HT, are manifestations of abnormal control mechanisms that develop slowly over long periods of time;3) it utilizes unique experimental models that mimic common forms of human HT, including obesity, preeclampsia, and postmenopausal-induced HT;4) it uses mathematical modeling and systems analyses to provide a conceptual framework for understanding cardiovascular dynamics and renal, endothelial, hormonal and neural mechanisms of HT. The research proposed in this application is described by the titles of the projects as follows: I. Neurohumoral and Renal Mechanisms of Hypertension: this project will elucidate the neurohumoral mechanisms, central nervous system (CNS) circuits and signaling pathways that mediate obesity induced SNS activation, impaired renal-pressure natriuresis, and HT as well as regulation of energy balance and metabolism;II. Endothelial Factors, the Kidney and Hypertension: this project will determine the role of obesity in altering multiple factors released by the placenta that cause endothelial dysfunction, impaired renal-pressure natriuresis, and HT during chronic reductions in uterine perfusion pressure in pregnancy. III. Hormonal and Intrarenal Mechanisms of Postmenopausal Hypertension: this project will determine the role of increased SNS activity, CNS signaling pathways, and intrarenal mechanisms that increase renal vascular resistance, blunt pressure natriuresis and raise BP in postmenopausal HT associated with hyperandrogenemia. The total program, including core support services, provides a unique interdisciplinary approach toward developing an integrative analysis of long-term regulation of BP and circulatory dynamics in forms of experimental HT that have great relevance to human HT.
OVERALL NARRATIVE Although considerable progress has been made in understanding the causes of hypertension and its impact on cardiovascular (CV) and kidney disease, suboptimal blood pressure control is still the number one attributable risk for death throughout the world. This program project application brings together investigators from multiple disciplines to focus on the mechanisms that contribute to impaired kidney function and increased blood pressure in experimental models that are highly relevant to common, and difficult to treat, forms of human hypertension associated with obesity, preeclampsia, and postmenopausal increases in androgen levels.
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