My laboratory investigates how cells make the decision to commit to programmed cell death. The BCL-2 family of proteins contains both pro-and anti-apoptotic members which interact to determine cell fate. We would like to understand in detail why different cells make different life/death decisions when confronted with the same initial perturbation. We are examining this question using protein biochemistry and proteomics, mouse modeling, cell biology and molecular biology. Specific areas of study include:
1) We are studying ways to identify systematically how insults like chemotherapy and growth factor withdrawal are communicated to the intrinsic (or mitochondrial) pathway of programmed cell death.
2) It is a well-known biological phenomenon that some cells seem readier to die than others. Can we define the biochemical basis for this predilection to die? Our recent work shows that “priming” of anti-apoptotic BCL-2 family members with certain pro-apoptotic members is responsible for certain cells being “primed” for death. We continue to study how broadly this can be applied in normal and cancer cells.
3) In general, it is poorly understood why some cells die when exposed to chemotherapy and others do not. We are investigating how the pretreatment apoptotic apparatus can govern chemosensitivity. Our ultimate goal is to apply these studies to primary cancer cells and predict chemosensitvity in the clinical setting.
4) Cancer cells violate many rules of normal cellular behavior, and thus often must endure tonic death signaling. Are cancer cells, but not normal cells, primed for death? Can we target this priming as a cancer selective targeted therapy?
5) Small molecule antagonists of anti-apoptotic BCL-2 proteins are in pre-clincal and clinical development. We have been studying these compounds to evaluate mechanism of action, and to determine predictors of cellular sensitivity. We have developed several assays which can accurately predict sensitivity to this class of compound. We are testing these in cell lines and primary human malignancies.
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