We are interested in exploring how cells regulate their survival and death. How does a cell decide whether to survive and cope, or trigger apoptosis in response to different stimuli? If the apoptotic pathway is activated, what is its mechanism and how is it regulated?
Cell death by apoptosis occurs extensively during development and is seen in many pathological conditions such as after stroke, neurodegenerative or cardiovascular diseases. In contrast, the inability of cells to undergo apoptosis is a fundamental hallmark of cancers. Therefore, understanding the mechanisms by which different cells regulate apoptosis has significant therapeutic implications.
We are particularly interested in identifying differences in the apoptotic pathway in postmitotic versus mitotic cells. An increased restriction of apoptosis is arguably beneficial for the long-term survival of postmitotic cells that have limited regenerative potential and perform critical functions. Thus, we are examining these questions in a variety of cells including cancer cells, as well as postmitotic cells such as neurons, cardiomyocytes, myotubes, and mitotic fibroblasts. Recently, we have also started examining apoptosis regulation in embryonic stem cells.
- We have found that the cytochrome c-mediated caspase activation pathway is tightly regulated in neurons, cardiomyocytes and myotubes, but not in fibroblasts, by the caspase inhibitory protein XIAP.
- We have identified dynamic changes involving chromatin restriction at the Apaf-1 promoter occurring with neuronal maturation to even further restrict the apoptotic pathway in mature neurons.
- We have found that mature neurons markedly upregulate a microRNA, miR-29, which acts to restrict apoptosis in neurons by targeting multiple members of the key BH3-only proapoptotic gene family.
- We have discovered a novel mechanism utilized by neurons and cancer cells involving glucose metabolism via the pentose phosphate pathway that inhibits apoptosis by directly inactivating cytochrome c.
Some Questions Currently Under Investigation:
Does XIAP deficiency make neurons more vulnerable to neurodegeneration?
Do neuronal soma and axons activate distinct pathways of degeneration?
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 between neurons and cancer cells?
How is apoptosis regulated in embryonic stem cells?