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，黑素瘤很可能是环境致癌物（如紫外线辐射）和基因之间相互作用的结果。迄今为止的证据表明，生长调节基因（如RAS和INK4alpha）的突变有助于CM的发展。然而，DNA修复在黑色素瘤发生中的作用尚不清楚。核苷酸切除修复（NER）的缺陷，如在临床疾病色素性干皮病中所见，导致发生CM的风险大大增加。然而，这种临床观察的机制在很大程度上是未知的。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。具体来说，拟议的研究将评估(1)正在进行的NER在限制自发黑色素瘤肿瘤生长方面是否至关重要；(2)在缺乏NER的情况下，除了RAS和INK4alpha之外，还出现了新的突变靶点；(3) INK4alpha的缺失破坏了ner缺陷细胞的UV反应。为了验证这些假设，候选人将使用小鼠模型来(I)在体内检查NER缺失对黑色素瘤形成的生物学后果；（II）在体外表征INK4alpha缺失对NER缺陷小鼠胚胎成纤维细胞（mef）紫外线反应的影响。对DNA修复机制的更彻底的了解可能会导致更好的预防和治疗策略。

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.