The general aim of our research program is to understand cellular and molecular Ca signaling mechanism for in vivo cardiovascular phenomena. Our research encompasses experimental approaches at all levels – clinical, whole animal, organ, tissue, cell, and molecular. Our clinical study in human diabetics on intravascular ultrasound imaging of coronary atherosclerosis guides our studies in swine that superbly mimic human atherosclerosis. We primarily study ion transport adaptations in cardiac and vascular endothelial and smooth muscle cells after several in vivo manipulations: 1) exercise training, 2) dyslipidemia, 3) metabolic syndrome (“pre-diabetes”), and 4) diabetes. Each condition requires chronic treatment of intact animals and study of isolated tissues and single cells from these animals. Our in vivo (whole animal) studies involve hemodynamic and insulin sensitivity measures. We are the only research group in the world with a breeding colony of Ossabaw swine that express metabolic syndrome, progression to type 2 diabetes, cardiac dysfunction, and profound atherosclerosis. We have characterized these swine extensively over the past ~14 years and provided Ossabaw widely beyond IUSM (e.g. Mayo Clinic), yielding a total of 106 published manuscripts. Organ level approaches utilize intravascular catheters, ultrasound, optical, and radiologic imaging, and localized gene targeting. Tissue level studies routinely involve culture of arterial segments and measurement of calcium and/or contraction. Typical cellular studies involve exposure of isolated cells to vasoactive agents in the metabolic syndrome and diabetic milieu (e.g. aldosterone), patch clamp electrophysiology, and fluorescence imaging. We have used multimodal nonlinear optical microscopy and vibrational photoacoustic imaging to characterize atherosclerotic lesions in our swine model. We are engineering catheters, drug delivery devices, and new compounds for early detection and treatment of diabetes and diabetes-induced complications. One molecular approach we use is to localize molecules within tissues and cells using several modes of microscopic imaging. With molecular cloning we have identified a novel adenosine A1 receptor, P2Y2 receptor, and TRPC channels that are regulated by several stressors and alter proliferation of coronary smooth muscle. We directly manipulate these potential molecular targets in vivo using drug-eluting stents and gene transfer via delivery catheters. A major goal is to prevent the progression of coronary smooth muscle Ca signaling from contractile to dedifferentiated proliferative, osteogenic, and apoptotic phenotypes in coronary disease. We have published more on coronary smooth muscle (CSM) intracellular Ca signaling and ion channels in health and in MetS/D over the past ~25 years than any group in the world. Our positron emission tomography-computed tomography (18F-NaF PET-CT) studies to image arterial calcification in vivo extend our Ca signaling studies further. I have 186 peer-reviewed publications (34 manuscripts in past 3 years) and trained 28 post-doctoral fellows, 18 PhDs.
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