ALTERATIONS OF CELL CYCLE CONTROL IN MELANOCYTIC LESIONS

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Developing and validating molecular pathogenesis models in human disease relies on the application of molecular biology techniques to the study of patient tissue specimens selected using the principles of epidemiology and biostatistics. As a dermatologist and molecular biologist, my goal is to use these techniques and principles in developing models of human melanocyte transformation. While my immediate goal is analyzing aberrent expression of cell cycle regulators in human melanocytic neoplasms, my long term goal is to translate these findings into new diagnostic techniques, prognostic models and therapeutic strategies. To achieve these goals I have chosen to investigate melanomas and dysplastic nevi from defined patient populations for alterations of the cell cycle regulators MDM-2 and p16. These molecules act in the p53 and pRb cell cycle control pathways, respectively. We have strong evidence for their role in the early stages of melanoma development. The career development plan I propose takes advantage of the exceptional combination of resources at the Memorial Sloan-Kettering Cancer Center, including the Division of Molecular Pathology, the Department of Epidemiology and Biostatistics and the Melanoma Prevention Program. My training will include applying the newest techniqes of molecular pathology, such as laser-capture microdissection and flourescent in-situ hybridization, to the analysis of human melanocytic neoplams. In addition, the development plan combines this experience with didactic and practical training in Epidemiology and Biostatistics. I will learn how to apply these principles to analyses that integrate molecular alterations in melanoma specimens with clinical paremeters. This combined training is essential for the proper design of future studies that will be needed to identify molecular targets for new therapuetic modalities which could be tested in clinical trials at Memorial Hospital. As new therapeutic modalities are capitalizing on advances made at the molecular level, I will have the background, training and experience to design and evaluate trials of new markers or drugs in the care of melanoma patients.