The overall goal of this Program Project is to generate basic knowledge concerning fundamental cellular mechanisms that mediate the normal intracellular environment essential for coordinated electrical and contractile function in heart and blood vessels. A unifying subtheme selected for this competitive renewal is Ca2+ ions and protein phosphorylation - interacting subcellular mechanisms of regulation in cardiac and vascular muscle. The broad specific aims that will be pursued through interactive and collaborative studies are: 1) to delineate key molecular mechanisms that account for the unique roles of the cholinergic and adrenergic limbs of the autonomic nervous system in regulating electrical and/or contractile function of cardiac and vascular muscle, 2) to identify and characterize pivotal protein kinase and/or phosphatase systems that commonly affect muscle electrophysiology or contractility through direct action on ion pumps, antiporters, channels or contractile and regulatory proteins, 3) to isolate and define the interaction of contractile and regulatory protein complexes that account for the unique force maintenance mechanism in vascular smooth muscle, a process that is dependent upon both Ca2+ and protein phosphorylation, and 4) to study specific ion channels, antiporters, or pump systems at the cellular and membrane level, elucidate specific molecular mechanisms of regulation and investigate interactions of these mechanisms at the intact tissue level. A variety of preparations or methodologies will be utilized in order to pursue the specific aims including cellular microelectrodes, perfused hearts, isolated cardiac myocytes, cultured cells, planar lipid bilayers, protein purification, monoclonal antibodies, protein sequencing, muscle mechanics, and recombinant DNA. This Program Project will produce a body of information that can serve as a logical paradigm for subsequent study of disease states such as cardiac arrhythmia and atherosclerosis.
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