Vascular occlusion or disruption resulted from stroke, or brain attack, can lead to brain ischemia and hypoxia that can result in serious neuronal injury. While damaged neurons often die from necrosis, significant amount of neurons die from apoptosis, or programmed cell death. Studies on the basic mechanisms of apoptosis have established that a group of cysteine proteases, i.e., caspases, are responsible for the execution of the death program. Caspases actively participate in the pathogenesis of ischemia/hypoxia-induced neuronal cell death, although how they are activated in this process is largely elusive. Bcl-2 family proteins are important apoptosis regulators and have been implicated in ischemic neuronal death. Two pro-apoptosis Bcl-2 family members, Bid and Bax, can activate caspases by triggering mitochondrial dysfunction including cytochrome c release. In our preliminary studies, we found that bid-deficient mice were significantly resistant to ischemic neuronal death in a focal ischemia model. In addition, mice deficient in both Bid and Bax demonstrated an even bigger resistance to the ischemic injury. Finally, at the molecular level, Bid and Bax can interact with each other and synergistically enhance each other's activity. We have thus formulated our hypothesis that both Bid and Bax are critical to the development of ischemia-induced neuronal apoptotic death by inducing mitochondrial dysfunction and activating the caspase cascade. Furthermore, while the two proteins may be activated by different mechanisms, they nevertheless accomplish the same goal of transmitting extracellular death stimuli to mitochondria and then initiate the execution in a collaborative fashion. We will test this hypothesis specifically from the following aspects: 1). To investigate the contribution of Bid and Bax to neuronal death in a murine focal ischemia model, 2). To define the role of Bid and Baxc in mitochondrial damage in neuronal cells with an in vitro neuronal injury model, and 3). To characterize the molecular interactions of Bid and Bax in inducing dysfunction of mitochondria isolated from the brain.
NIH ExPorter
NIH ExPorter