Brain-Derived Neurotrophic Factor and Sympathoexcitation in Chronic Heart Failure

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 DESCRIPTION (provided by applicant): The primary objective of this project is to determine the role of Brain-Derived Neurotrophic Factor (BDNF) in modulation of sympathetic nerve activity (SNA) and K+ channel activity in response to Angiotensin II (Ang II) and its potential rol in cardiovascular disease states such as chronic heart failure (CHF). Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with CHF contributing to a substantial number of these cases. Although numerous factors influence the outcome of CHF, increases in SNA, which is dependent on the activity and sensitivity of specific brainstem neurons, are associated with an increase in complications and a higher mortality rate during the progression of CHF. The discharge sensitivity of neurons depends on the magnitude of outward K+ currents, which when decreased promote excitability. Factors such as Angiotensin (Ang) II and reactive oxygen species, which are elevated in the brains of animals with CHF, can decrease K+ currents. In a search for additional factors that may impact sympathetic outflow in CHF, we examined the role of Brain-Derived Neurotrophic Factor (BDNF) which has also been shown to suppress K+ currents and may interact with Ang II. Based on previous studies in which BDNF has been given centrally it is likely that this protein may contribute to sympathoexcitation in CHF. Therefore, based on evidence from the literature and our preliminary experiments, we hypothesize that in states where Ang II is elevated, such as CHF, increased neuronal BDNF expression and signaling along convergent pathways contributes to the suppression of K+ currents and promotes neuronal excitability. To investigate this hypothesis three specific aims are proposed. In Specific Aim 1, the link between Ang II and BDNF in causing increased activation of convergent signaling pathways and elevated ROS levels will be investigated in cell culture and a rat model of CHF. In Specific Aim 2, patch clamp electrophysiology experiments will investigate the potential sites of interaction between Ang II and BDNF in decreasing K+ currents and increasing neuronal excitability in neuronal cell lines and primary neuronal cultures. In Specific Aim 3, direct central administration of BDNF or antagonists to BDNF signaling will be administered to a rat model of CHF to investigate the contribution of this factor to the progression of CHF. A comprehensive pre-doctoral training program is described with the goal of sharpening and broadening research skills of the applicant.