Nucleotide Excision Repair in Cutaneous Melanoma

皮肤黑色素瘤的核苷酸切除修复

基本信息

批准号：
7269854
负责人：
HENSIN TSAO
金额：
$ 13.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2008-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在过去的几十年中，皮肤黑色素瘤（CM）的发生率已大大增加。像其他癌症一样，黑色素瘤很可能是由于环境致癌物（例如紫外线辐射和遗传学）之间的相互作用而引起的。迄今为止的证据表明，生长调节基因（例如RAS和INK4ALPHA）的突变有助于CM的发展。然而，不太了解的是DNA修复在黑色素瘤肿瘤发生中的作用。如临床疾病外那症色素色素中所见，核苷酸切除修复（NER）的缺陷导致发生CM的风险极大地夸大了。然而，这种临床观察的基本机制在很大程度上没有表征。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理中的作用。具体而言，拟议的研究将评估（1）持续的NER对于限制自发性黑色素瘤肿瘤生长至关重要。（2）在没有NER的情况下出现Ras和Ink4alpha以外的突变靶标的新颖靶；（3）Ink4Alpha的丢失会破坏缺陷细胞中的紫外线反应。为了检验这些假设，候选人将使用鼠模型来（i）在体内检查NER丧失对黑色素瘤形成的生物学后果，并且（ii）在体外表征Ink4alpha丢失对NER缺乏鼠类缺乏鼠类胚胎胚胎纤维纤维纤维细胞（mefs）的UV反应的影响。对DNA修复机制的更透彻的了解可能会导致更好的预防和治疗策略。 Tsao博士同时获得了医学博士学位和博士学位。来自哥伦比亚大学。在完成皮肤病学的居留权后，他回到实验室，以专注于人类黑色素瘤遗传学。通过拟议的研究，他正在与以前的研究急剧脱离，并将自己浸入癌症遗传学中。 Tsao博士是哈佛医学院皮肤病学助理教授，也是马萨诸塞州综合医院黑色素瘤中心的副医师。 Tsao博士致力于研究皮肤黑色素瘤，本申请中概述的职业发展活动将使他完全独立。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice.

色素性干皮病 C (Xpc) 的缺失会增强 Ink4a-Arf 缺陷小鼠的黑色素瘤光致癌作用。

DOI：
10.1158/0008-5472.can-06-3806
发表时间：
2007
期刊：
Cancer research
影响因子：
11.2
作者：
Yang,Guang;Curley,David;Bosenberg,MarcusW;Tsao,Hensin
通讯作者：
Tsao,Hensin

Cutaneous Presentation of Mesothelioma With a Sarcomatoid Transformation.

间皮瘤伴肉瘤样转化的皮肤表现。

DOI：
10.1097/dad.0000000000001023
发表时间：
2018
期刊：
The American Journal of dermatopathology
影响因子：
0
作者：
Klebanov,Nikolai;Reddy,BobbyY;Husain,Sameera;Silvers,DavidN;Grossman,MarcE;Tsao,Hensin
通讯作者：
Tsao,Hensin