This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over-expression of sigma receptors in tumors and in tumor cell lines of various tissue origins is well documented and underscores the putative essential role of sigma receptors in the pathophysiology of cancer. In regards to the sigma-1 receptor specifically, its transient overexpression in cells is partially protective against apoptotic stimuli while gene silencing of the receptor leads to a statistically significant decrease in proliferation of breast cell lines. Even though endogenous ligands for the sigma receptors have not yet been identified, activation of sigma-1 receptors using small molecule agonists appears to further extend its """"""""apoptosis resistance"""""""" abilities. More interesting, antagonism of the sigma-1 receptor reverses this effect causing tumor cell loss due to programmed cell death. Clearly, the sigma-1 receptor is an exciting new potential biomarkers for cancer diagnosis and is also an important target for therapeutic intervention. Our objective is to define how the sigma-1 receptor mediates its control over cellular survival signals;and due to its ability to bind cholesterol and modulate the lipid composition of lipid rafts, we hypothesize that the sigma-1 receptor uses a network of interacting proteins to translate ligand binding events into biological action via a lipid-raft dependent pathway. Therefore, we plan to accomplish the objective of this pilot project by pursuing one specific aim: Identify proteins that modulate their association with lipid-rafts in a sigma-1 receptor signaling-dependent manner using proteomic technology.
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