Our long-term goal is to identify the neuronal mechanisms of elevated sympathetic outflow in chronic heart failure (CHF) and provide new targets for treatments of CHF. The objective here is to determine the molecular mechanisms of down-regulation of SK channel function among autonomic PVN neurons and the contribution to sympathetic activation in CHF. Our central hypothesis is that upregulation of microRNA-9-3p is involved in the diminished SK current and expression in autonomic PVN neurons, which contributes to the sympathetic activation in CHF. The rationale for the proposed research is that once the mechanism is known of how 1) SK current is reduced among PVN neurons and 2) diminished SK current contributes to the sympathetic activation in CHF, the data will contribute to new and innovative approaches to the prevention and treatment of CHF. We will test our central hypothesis and accomplish the overall objective by pursuing the following specific aims: 1. To determine the role of miR-9-3p among autonomic PVN neurons in regulating SK current, expression, excitability and sympathetic activation in CHF in vivo. Our working hypothesis is that overexpression of miR-9-3p diminish SK current and expression, thus contributing to increased excitability of autonomic PVN neurons and sympathoexcitation in CHF. 2. To determine the role of miR-9-3p in mediating post-transcriptional inhibition to SK channels expression, SK currents and excitability NG108 and primary culture brain neuron cells in vitro. Our working hypothesis is that upregulation of miR-9-3p is involved in the down-regulation of SK channel expression in the neuron in vitro. 3. To establish an integrated research and educational program in integrative physiology. My training in neuro- and cardiovascular-physiology as well as research expertise that includes electrophysiological techniques and integrative physiology approaches have provided me unique skills to establish distinguished and discovery-based learning environments for both undergraduate and graduate levels.
Chronic heart failure (CHF) is a major risk factor for cardiovascular disease, morbidity and mortality. The work proposed is expected to identify the components responsible for the increased neuronal excitability and elevated sympathetic outflow CHF. Such results are expected to have a positive impact on providing insight into the neuronal mechanisms of CHF and identify components to provide new targets for preventive and therapeutic interventions in salt retaining cardiovascular disease.
