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. Malignant melanoma is the deadliest form of skin cancer that continues to increase in incidence at a rate of 3% per year. Melastatin (TRPM1) was discovered as a gene down-regulated in highly metastatic tumors in mice and humans, suggesting that TRPM1 expression may be an indicator of melanoma aggressiveness. This finding raised the interesting possibility that TrpM1 might be a tumor suppressor, an unprecedented function for an ion channel. Despite being the founding member of the TrpM family of ion channels, very little is known about the molecular properties and cellular functions of TrpM1. The goal of the proposed research is understanding the function of TrpM1 and the connection between TrpM1 and melanoma. Determining the molecular mechanisms by which TrpM1 is involved in normal and malignant cells could lead to significant progress in the diagnostic and treatment of melanoma. To understand the role of TrpM1 in cellular function, it is critical to characterize its sub-cellular localization and cellular dynamic. To express fluorescently tagged TRPM1 in primary human melanocytes and melanoma cells we will use a lenti-viral system. We will then employ confocal imaging, total internal reflection fluorescence (TIRF) and electron microscopy (EM) to determine the intracellular versus plasma membrane distribution of TrpM1, the dynamic properties of the intracellular structures containing TRPM1 and their identity. The results of the proposed experiments will represent a significant step towards understanding the function of TrpM1 in melanocytes.
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