Apoptosis is fundamental to a plethora of diseases for which effective treatments are currently lacking, including stroke, heart disease, neurodegenerative diseases, and cancer. An understanding of the events that occur leading up to the induction of apoptosis has the potential to provide numerous pharmacological agents that could control apoptosis and lessen the damage following stroke. The broad, long-term objectives of the research proposal are to elucidate the mechanism(s) for release of proapoptotic factors from the mitochondria during apoptosis on the biophysical and molecular level The immediate goals are to determine the mechanisms by which the permeability of the mitochondrial outer membrane is changed in the events that determine whether apoptosis will proceed or not- Conflicting results published by leading researchers emphasize the need for carefully controlled experiments and for an experimental plan that seeks to achieve definitive results. The research proposal specifically focuses on the role of ceramide channels in induction of cytochrome c release from the intermembrane space of the mitochondria to the cytoplasm. At least three different experimental approaches will be utilized, namely the planar membrane technique, liposomes, and mitochondrial suspensions, in an effort to obtain definitive results that can further the field of apoptosis. Both characterization of the ceramide channels and the potential interactions between ceramide channels and pro- and anti-apoptotic members of the bcl-2 family is included.
| Siskind, Leah J; Kolesnick, Richard N; Colombini, Marco (2002) Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem 277:26796-803 |
| Siskind, L J; Colombini, M (2000) The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J Biol Chem 275:38640-4 |
