This report describes the progress of the research performed during the first 3.5 years of the R37 award. The research has focused on the protective and cytotoxic actions of nitric oxide in liver cells in two interrelated aims.
Under Aim I we proposed to determine how cellular redox status regulates the chemical fate and function of nitric oxide in hepatocytes. We have shown that the consequences of NO exposure on hepatocytes dependent on cell redox stress. We have also partially characterized denitrosation activityin liver cells. We have discoveredthat the inducible nitric oxide synthase (iNOS) translocates to the peroxisome in hepatocytes. This enzyme exhibits decreasedspecific activity. This may be a mechanism to shuttle dysfunctional enzyme out of the cell.
Under Aim II we determine how cyclic nucleotides prevent apoptosis. We have shown that cGMP and cAMP block the proximal events in apoptotic signaling. Furthermore, we have begun to explore novel and important areas in our research. Specifically, we have demonstrated that FADD levels increase dramatically in response to apoptotic stimuli. Furthermore, we have demonstrated that death inducing signaling complex (DISC) components translocate to the mitochondria during apoptotic signaling. TNF receptor also translocates to the mitochondria following TNF stimulation. These observations are described in the progress report. We also detail our plans to pursue these novel findings in the future.
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