Department of Pathology & Laboratory Medicine
CARDIOVASCULAR BIOLOGY:
The major overall goals of Dr. Ashraf's research program are to elucidate the subcellular and molecular mechanisms of ischemia/reperfusion injury in the myocardium and its prevention by therapeutic interventions. The current focus is on the ischemic preconditioning which is myocardial adaptive response to short episodes of subcellular ischemia that triggers cardiac tolerance to lethal ischemia. Identifying the mechanisms by which preconditioning protects the heart may lead to the development of novel therapeutic strategies of salvaging ischemic myocardium in patients with coronary artery disease. Potential involvement of adenosine, calcium, oxygen radicals (nitric oxide) via a signaling cascade involving protein kinase C with mitochondrial KATP channel as the end effector of protection in acute phase as well as synthesis of cardioprotective proteins in late phase (after 24 hours) are being investigated. The central hypothesis in the late protection is that the upregulation of iNOS occurs by the initial ischemic stimulus via protein kinase C and nuclear factor kB and upon ischemia NO is released activating the mitochondrial KATP channel for the protection. This is the first proposal that identifies mitoch K-ATP channel as the end effector of protection in both acute and late preconditioning via NO/PKC signaling pathway. Since this channel can be activated with clinically used substances, such as diazoxide and morphine, this channel represents a novel therapeutic strategy against ischemic injury.The studies utilize both isolated perfused and intact hearts from normal transgenic and knockout mice, myocyte cell cultures as experimental models. A wide range of multidisciplinary techniques involving cell biology, biochemistry, molecular biology, immunocytochemistry, fluorescence and electron microscopy, apoptosis and pharmacological approaches are being used to integrate the information at the cell level with the function at the organ level.
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