ALTERATIONS OF CELL CYCLE CONTROL IN MELANOCYTIC LESIONS

开发和验证人类疾病的分子发病模型依赖于应用分子生物学技术来研究利用流行病学和生物统计学原理选择的患者组织标本。作为一名皮肤科医生和分子生物学家，我的目标是将这些技术和原理用于开发人类黑素细胞转化的模型。虽然我的近期目标是分析细胞周期调节因子在人类黑素细胞肿瘤中的异常表达，但我的长期目标是将这些发现转化为新的诊断技术、预后模型和治疗策略。为了实现这些目标，我选择了研究黑色素瘤和发育不良痣患者群体中细胞周期调节因子MDM-2和p16的变化。这些分子分别作用于p53和pRb细胞周期控制通路。我们有强有力的证据证明它们在黑色素瘤发展的早期阶段所起的作用。我提出的职业发展计划利用了纪念斯隆-凯特琳癌症中心的特殊资源组合，包括分子病理学部门、流行病学和生物统计学部门以及黑色素瘤预防计划。我的培训将包括应用最新的分子病理学技术，如激光捕获显微解剖和荧光原位杂交，来分析人类黑素细胞肿瘤。此外，发展计划将这一经验与流行病学和生物统计学的教学和实践培训结合起来。我将学习如何将这些原理应用于将黑色素瘤标本中的分子变化与临床参数相结合的分析。这种综合培训对于正确设计未来的研究至关重要，这些研究将需要确定新疗法的分子靶点，这些新疗法可以在纪念医院的临床试验中进行测试。随着新的治疗方式利用在分子水平上取得的进展，我将拥有设计和评估用于治疗黑色素瘤患者的新标记物或药物的试验的背景、培训和经验。

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.