RESEARCH INTERESTS

Our overall research interests are in understanding how mammalian cells activate the programmed cell death pathway and die by apoptosis. We have focused our work on examining this pathway in postmitotic cells such as neurons, cardiomyocytes, and myotubes. Cell death by apoptosis occurs extensively during development and is seen in many pathological conditions such as after stroke, neurodegenerative or cardiovascular diseases. Therefore, understanding the mechanism by which neurons, cardiomyocytes, and myotubes undergo apoptosis has important therapeutic implications. Recently, we have also begun to examine this pathway in stem cells and in various cancer cells.

Specifically, we are investigating the molecular events that regulate the activation of caspase proteases during neuronal apoptosis. We have described a novel pathway that is necessary for caspase activation and apoptosis in postmitotic neurons but not in most mitotic cells. We have identified the XIAP protein as the critical component of this pathway and are examining the molecular mechanism by which XIAP regulates apoptosis in neurons. We are also investigating whether the apoptotic pathway shows any changes in its regulation as neurons mature and age. We have identified four distinct stages by which apoptosis becomes increasingly regulated in neurons with age. We are currently investigation the molecular mechanism of these novel changes and examining how these changes could be reversed to permit apoptosis to occur in adult neurons in the context of neurodegeneration.

Most recently, we have also found that the regulation of caspase activation in postmitotic cardiomyocytes and skeletal muscle cells is strikingly similar to that seen in neurons. These data point to the exciting possibility that there may be a fundamental difference is the regulation of caspase activation between mitotic and postmitotic cells. Examining this hypothesis using various approaches is a major focus of our current and future research.

Current Questions under Investigation:

-Does XIAP deficiency make neurons more vulnerable to neurodegeneration?

-How does the apoptotic pathway change its regulation with maturation and aging?

-Are there fundamental differences in the regulation of the apoptotic pathway in mitotic versus postmitotic cells?

-Can we identify microRNAs that regulate apoptosis in mammalian cells?

-Are there common mechanisms of apoptosis regulation in stem cells and cancer cells?

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