During the past decade, the major research focus of the heme oxygenase-1 (HO-1) field has shifted from the study of an essential rate limiting enzyme of heme catabolism to the current emphasis and interest of an intriguing cytoprotective molecule. Although the precise mechanism by which HO-1 imparts potent cytoprotective effects against cellular stresses is still poorly understood, accumulating evidence suggest that the catalytic by products of HO-1 such as biliverdin/biluribin, ferritin and carbon monoxide (CO) may serve as critical mediators of HO-1's cytoprotection. In particular, our laboratory and others have demonstrated that CO confers potent cytoprotection via anti-inflammatory, anti-proliferative and anti-apoptotic effects. Recent reports have started to unravel the mechanisms and signaling pathways by which CO imparts anti-inflammatory and anti-proliferative effects in various models of cellular and tissue injury. In contrast, the mechanism by which CO imparts anti-apoptotic effects is less well known and less well studied. During the latter part of the funding period of this HL-55330 grant, we have obtained preliminary data that CO's imparts anti-apoptotic effects by regulating both extrinsic and intrinsic cell death pathways. In addition, we have obtained new preliminary data which demonstrate for the first time subcellular compartmentalization of HO-1 in the mitochondria, an organelle critical in regulating apoptosis in response to oxidative stress. Thus, for the competitive renewal of this grant, based on our published work and Preliminary Studies, we have chosen to propose studies to test the following hypothesis: Hypothesis: CO mediates antiapoptotic effects by regulating both the extrinsic and intrinsic cell death pathways and that subcellular localization of HO-1 in the mitochondria plays an important role in contributing to the cytoprotection of HO-1 against oxidative stress. We will test our hypothesis by addressing the following specific aims: 1) To determine the mechanism(s) by which CO attenuates the """"""""extrinsic"""""""" death receptor mediated cell death pathway 2) To determine the mechanism(s) by which CO attenuates the """"""""intrinsic"""""""" mitochondria dependent cell death pathway 3) To determine the mechanism(s) by which reactive oxygen species (ROS) mediates CO's attenuation of both extrinsic and intrinsic cell death pathways.
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