This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The renin-angiotensin system (RAS) is a major regulation of cardiovascular (CV) and renal function in health and disease. The common assumption was that angiotensin-II (ANG-II) served as the main actor of this system. A new member of the RAS, ACE2 (angiotensin converting enzyme type 2) has been identified in organs and tissues related to CV function (e.g. heart, kidney, vessels) and appears to be part of a counter-regulatory pathway buffering the excess of Ang-II. We recently identified the ACE2 protein in the brain in regions involved in the central regulation of blood pressure and showed that it was regulated by other components of the RAS. These observations added to the role of ACE2 in the generation of biologically active peptides supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that ACE2 is a functional element of the brain in RAS and its down-regulation leads to the development of hypertension. Taking advantage of our expertise in physiological genomics, a science that studies the physiological consequences of gene manipulation, combined to state of the art recording and analysis of CV function and conscious mice, we propose to investigate the effects of transient and chronic ACE2 overexpression on the central regulation of blood pressure and the development of hypertension. Using genetically-engineered mice with brain-targeted ACE2 overexpression and adenovirus-mediated delivery of an ACE2 transgene, we will address the following questions: 1) What are the functional consequences of overexpression of ACE2 in the brain of normal mice? 2) Does chronic ACE2 overexpression in mouse brain prevent or delay the development of hypertension? 3) Does ACE2 overexpression affect Ang-II signaling pathways? We believe that these unique models and gene-targeting approaches will allow us to determine the physiological role of central ACE2 in vivo in hypertension. Evidence of a role of ACE2 in hypertension could lead to the development of new therapeutics as well as a better utilization of existing therapeutics for the treatment of hypertension and other CV diseases.
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