Grant: $247,858 - National Institutes of Health - Jul. 17, 2009
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Award Description: The goal of this proposal is to establish pre-clinical evidence of synergism between glucocorticoids such as dexamethasone (Dex) and the MEK inhibitors such as PD184352 in the induction of apoptosis in acute lymphoblastic leukemia (ALL) cells. Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including ALL. GC-induced apoptosis involves the intrinsic mitochondria-dependent pathway, but the signaling pathways and downstream target molecules involved in GC-induced cell death are not entirely clear. We and others have previously shown that BIM (BCL- Interacting Mediator of cell death), a pro-apoptotic BCL-2 family protein, is up-regulated by Dex treatment in ALL cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation by survival/growth factors. We therefore hypothesize that co-treatment with Dex and MEK/ERK inhibitors will promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. Significantly, preliminary data from our laboratory demonstrate that MEK inhibitors synergistically promote DEX lethality in a variety of ALL cell lines. We now propose to elucidate the mechanisms by which MEK/ERK inhibition enhances the activity of BIM and perturbs other pro- and anti-apoptotic BCL-2 family members to enhance Dex efficacy in ALL cells. The specific aims are to 1) evaluate the significance of BIM-dependent/-independent pathways and the BIM phosphorylation status in apoptosis with Dex and MEK inhibitors co-treatment; 2) determine the molecular mechanisms how BIM is induced by dexamethasone treatment; 3) employ in vivo murine models of ALL to establish a basis for the efficacy of the strategy.
Project Description: Progress is being made towards all aspects of the project as described in the Award Description field
Jobs Summary: 1 animal technician (part-time) and 1 post-doctoral fellowship (full time)created (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 17, 2009. Help expand these official descriptions using the wiki below.