The candidate's long-term goal is to develop a career in cardiovascular research as an independent investigator. This project will be developed at the Masonic Medical Res. Lab., a well-established institution in cardiovascular research, under the direct mentorng of Dr. Antzelevitch, head of the institute. Dr. Antzelevitch, will guide this applicant in his career development plan as well as in his research project. An extramural consultation with Dr. Nelson, is also planned to better help this applicant's research potential. The career development plan includes course attending, weekly reports, oral presentations, scientific meeting attending, publication preparation and submission, and extramural collaborations with Dr. Escobar to learn """"""""state of the art"""""""" biophysical techniques proposed in this application. The research project will investigate fundamental remaining questions about the actual mechanisms of the beta1 of the KCa channels in its native environment, as well as to explore potential roles for future therapeutic approaches. The disruption of the beta1 subunit leads to severe consequences such as increased arterial tone, elevated blood pressure and enlarged heart size. However, the very nature of the molecular mechanisms involved in this vasoregulation and the potential involvement of this protein in vasodilatory pathways has yet to be investigated. This proposal seeks to provide an integrated picture of how the beta1 subunit modifies KCa channel behavior based on quantitative measurements.
The specific aims of this proposal will be addressed in a series of experimental objectives designed to dissect the molecular components of KCa channel function. These objectives are intended to define the role of the beta1 subunit in native arterial smooth muscle KCa channels, in terms of their voltage sensitivity, calcium sensitivity, activation kinetics, channel-toxin interaction and channel distribution. They will also try to identify the involvement of the beta1 subunit in the activation of KCa channels in vasodilatory pathways mediated by protein kinases (PKG and PKA) and in the direct action of estradiol on KCa channels as a possible non genomic vasodilatory effect of estradiol. This study should provide fundamental quantitative bases to understand the molecular tuning of a potassium channel highly relevant to vasoregulation and blood pressure.
