UVR-INDUCED MELANOCYTIC NEVI AND PROGRESSION TO MELANOMA

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The overall objective of this project is to further develop the laboratory opossum, Monodelphis domesitica, as a unique model for investigations of melanocytic skin lesions induced by exposure to ultraviolet radiation (UVR) alone. Monodelphis is the only mammalian laboratory species that is available for experimental examination of the events associated with melanoma induction and progression by UVR exposure alone, without the complicating factors of chemical enhancers or promoters. The complex and only partially understood etiology, and the increasing incidence of human melanoma, underscore the importance of further biomedical research on this serious threat to human health. We have used a novel and promising method for UVR initiation of melanoma in Monodelphis which involves exposure at the neonate (suckling) stage. In this project we aim to establish optimal conditions for UVR exposure of neonates that will allow the most economical production of informative lesions. We intend to characterize the clinical and pathological progression of neonatally initiated lesions to malignant melanoma and to determine the nature and extent to karyotypic changes that are associated with metastatic melanomas and cell lines derived from them. After identification of pedigrees with individuals to establish high and low susceptibility lines. Using appropriate breeding strategies, these lines can then be used to investigate the genetic regulation of the multistage process of melanoma formation and ultimately to identify and characterize the genes involved. An important component of this project is to make available data, animals, or tissues arising from the neonate irradiation studies to the Core Unit and to other projects. Lesion incidence data for the detection of any major gene effect on susceptibility will be supplied to the Core Unit; animals with melanoma will be supplied to Project 3 for efficacy testing of candidate chemotherapeutic compounds; and tissues from affected and unaffected individuals for allelic association studies at candidate tumor suppressor and oncogene loci will be supplied to Project 6.