The focus of the Neuroapoptosis Laboratory at the University of Pittsburgh Department of Neurological Surgery is the study of the basic mechanisms of apoptosis, as mediated by the caspase apoptotic family in neurologic diseases. In addition, discovering novel approaches to ameliorate the impact of cell death in a variety of neurological diseases is a central theme of the Neuroapoptosis Laboratory.
We are evaluating the impact apoptotic cell death, and in particular, that mediated by the caspase cell death family on the pathogenesis of neurodegenerative diseases. Neurodegenerative diseases presently being investigated are Amyotrophic Lateral Sclerosis (ALS) as well as Huntington’s Disease (HD). Activation of the caspase cell death cascade appears to play an important role in a variety of neurodegenerative diseases. We have demonstrated that inhibition of the Caspase-1 (also known as ICE) apoptotic gene slows the progression and delays mortality in transgenic mouse models of ALS and Huntington’s disease. Furthermore, delivering caspase inhibitors directly in to the brain of these transgenic mice prolongs their survival. This was the first time that any intervention had been demonstrated efficacious in a HD model. Adding relevancy to these findings, we have also demonstrated that caspase-1 is activated in the brain and spinal cord of humans with HD and ALS respectively. We have also demonstrated that Minocycline demonstrates neuroprotection in a mouse model of HD.
Apoptotic cell death plays a significant role in stroke as well as traumatic brain and spinal cord injury. We are evaluating the impact ICE family activation has on apoptotic cell death in these conditions. The relation of the caspase family and free radical production is also being investigated. Targeted caspase-mediated pharmacoprotection is also being investigated.
Using in vitro models, we are evaluating both the mechanisms involved in the activation of ICE, as well as the post-ICE activation pathways involved cell death. The role of Interleukin-1b in apoptosis continues to be a focus of research. We are also continuing to evaluate the basic mechanisms of cell death, and especially as they relate to neurologic diseases.