This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The overall objective of this proposal is to understand the molecular mechanisms within cells that cause and protect against cadmium toxicity. We propose to develop an in vitro model using cell lines that exhibit differential sensitivity to cadmium 1) to study the molecular mechanisms within cells involved in cadmium resistance and toxicity, and 2) to test the cytotoxicity of newly-synthesized cadmium-sequestering molecules. We have identified two cell lines that possess different sensitivity to cadmium exposure; a human osteosarcoma cell line (Saos-2) and a rainbow trout gill cell line (RT gill-W1). We will investigate cadmium induced cell death by necrosis and apoptosis, and demonstrate that these cell lines can be used as an experimental model. In collaboration with Dr. Peter Craig, the in vitro model will be used to screen the cytotoxicity of newly synthesized cadmium-sequestering molecules. Dr. Sheryl Hawkes will quantify the effect of cadmium and cadmium-sequestering molecules in the two cell lines by performing proteome analysis. Individual proteins of interest will be studied that exhibit changes to their post-translational modifications or up- or down-regulation in response to cadmium or cadmium-sequestering agents.
The specific aims to be tested include: 1) We will test the hypothesis that RT gill W1 cells are more resistant to cadmium-induced cell death compared to Saos-2 cells; 2) We will determine whether cadmium-sequestering molecules reduce cadium-induced cell death; 3) We will compare the differences in cadmium-altered protein expression in the two cell lines; and 4) We will determine whether cadmium-sequestering molecules alter protein expression in these two cell lines.
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