Nucleotide Excision Repair in Cutaneous Melanoma

描述(由申请人提供)：在过去的几十年里，皮肤黑色素瘤(CM)的发病率急剧增加。像其他癌症一样，黑色素瘤很可能是由环境致癌物(如紫外线辐射)和遗传学之间的相互作用造成的。到目前为止的证据表明，生长调节基因的突变，如RAS和INK4Alpha，有助于CM的发展。然而，人们对DNA修复在黑色素瘤发生中的作用知之甚少。核苷酸切除修复(NER)的缺陷，如临床疾病色素性干皮病，导致发生CM的风险被大大夸大。然而，这种临床观察背后的机制在很大程度上还没有确定。该项目的长期目标是了解核苷酸切除修复在皮肤黑色素瘤发病机制中的作用。具体地说，拟议的研究将评估是否(1)正在进行的NER在限制自发黑色素瘤肿瘤生长方面至关重要；(2)在没有NER的情况下，除了RAS和INK4α之外，还会出现新的突变靶点；(3)INK4α的丢失扰乱了NER缺陷细胞中的紫外线反应。为了验证这些假设，候选人将使用小鼠模型来(I)在体内检测NER缺失对黑色素瘤形成的生物学后果，以及(Ii)在体外表征INK4Alpha缺失对NER缺乏的小鼠胚胎成纤维细胞(MEF)紫外线反应的影响。更彻底地了解DNA修复机制可能会导致更好的预防和治疗策略。 曹博士在哥伦比亚大学获得医学博士和博士学位。在完成皮肤科实习后，他回到实验室，专注于人类黑色素瘤遗传学。通过拟议的研究，他戏剧性地背离了以前的研究，沉浸在老鼠癌症遗传学的研究中。曹医生是哈佛医学院皮肤科助理教授和马萨诸塞州综合医院黑色素瘤中心的副内科医生。曹博士致力于皮肤黑色素瘤的研究，申请书中概述的职业发展活动将使他完全独立。

DESCRIPTION (provided by applicant): The incidence of cutaneous melanoma (CM) has dramatically increased over the past several decades. Like other cancers, melanomas most likely result from an interaction between environmental carcinogens, such as ultraviolet radiation, and genetics. Evidence so far suggests that mutations in growth regulatory genes, such as RAS and INK4alpha, contribute to the development of CM. Less understood, however, is the role of DNA repair in melanoma tumorigenesis. Defects in nucleotide excision repair (NER), as seen in the clinical disorder xeroderma pigmentosum, lead to a greatly exaggerated risk of developing CM. The mechanism, however, underlying this clinical observation is largely uncharacterized. The long-term objective of this project is to understand the role of nucleotide excision repair in the pathogenesis of cutaneous melanoma. Specifically, the proposed studies will evaluate if (1) ongoing NER is critical in restricting spontaneous melanoma tumor growth; (2) novel targets for mutation in addition to RAS and INK4alpha emerge in the absence of NER; (3) loss of INK4alpha disrupts the UV response in NER-deficient cells. To test these hypotheses, the Candidate will use murine models to (I) examine, in vivo, the biological consequence of NER loss on the formation of melanomas and (II) characterize, in vitro the impact of INK4alpha loss on the UV-response in NER-deficient murine embryonic fibroblasts (MEFs). A more thorough understanding of the DNA repair mechanisms could lead to better strategies for prevention and therapy. Dr. Tsao received both his M.D. and Ph.D. from Columbia University. After completing a residency in Dermatology, he returned to the laboratory in order to focus on human melanoma genetics. With the proposed studies, he is taking a dramatic departure from previous studies and immersing himself in mice cancer genetics. Dr. Tsao is an Assistant Professor of Dermatology at Harvard Medical School and an associate physician at the Massachusetts General Hospital Melanoma Center. Dr. Tsao is committed to the study of cutaneous melanoma and the career development activities outlined in this application will allow him to become fully independent.