Epigenomic mechanisms of skin carcinogenesis

项目总结 皮肤癌已经是美国最常见的癌症，由于 娱乐性阳光暴晒和美国人口老龄化的综合影响。这项提议将 将强大的全基因组表观遗传学技术应用于人类患者样本以及体外和体内模型 确定皮肤表观基因组的变化如何驱动皮肤癌变，并鉴定染色质 可能作为预防和治疗目标的修饰剂。通过关注表观基因组的作用 角质形成细胞癌的促进中的失调，这个项目直接涉及角质形成细胞生物学 NIAMS的疾病和疾病计划，并具体解决NIAMS 2015-2019年长期目标 计划，包括研究染色质结构和皮肤的表观遗传机制。候选人： 布莱恩·卡佩尔于2009年在纽约大学获得医学博士学位。2013年，他获得了董事会认证 在宾夕法尼亚大学皮肤科住院医师课程完成后。他目前 宾夕法尼亚大学皮肤病学系和表观遗传学项目的讲师和博士后研究员， 在实验室接受培训，专门了解癌症和癌症的表观遗传机制 衰老。这项建议建立在他对细胞衰老和遗传学的既定兴趣之上，将产生 新的科学成果，并为候选人提供批判性培训。申请人的长期目标 是成为R01资助的独立研究员，研究表观遗传机制如何对皮肤做出贡献 疾病。环境：卡佩尔博士的导师谢利·伯杰博士提供了无与伦比的专业知识。伯杰博士是 她以表观遗传学、染色质结构和功能在基因组调控方面的研究而闻名世界。 在她的整个职业生涯中，她一直得到美国国立卫生研究院的资助，并为这项工作提供了广泛的资源 本提案中所描述的。伯杰博士在指导方面也有良好的记录。申请人的职业生涯 发展计划需要在表观遗传技术和计算生物学方面进行严格的培训，包括 这些领域的课程工作对他的成功至关重要，并得到了多样化和专注的 科学顾问。此外，卡佩尔博士还得到了宾夕法尼亚大学皮肤科的全力支持。 研究：卡佩尔博士的初步结果显示，细胞衰老过程中的炎症，即众所周知的 衰老相关分泌表型(SASP)可被新型表观遗传药物减弱。这 通过消除DNA损伤反应激活和直接修改局部染色质而发生 环境对SASP基因的影响。表观基因组如何改变并驱动皮肤癌的发生尚不清楚。 明白了。正如最近的研究表明，仅有基因突变不足以 皮肤癌的发展，研究人员假设对表观遗传过程的理解 在皮肤癌发生的早期阶段，可能为预防和治疗提供新的机会。 这项提议将以卡佩尔博士的初步数据为基础，1)定义全球表观基因组和转录 在皮肤光老化和致癌过程中发生的变化，以及2)确定染色质调节剂可以 以防止紫外线诱导的表观基因组改变和致癌转化为目标。建议数 科学研究，伯杰博士的指导，以及候选人部门和 咨询委员会将使卡佩尔博士能够作为一名独立的内科科学家开始成功的职业生涯。

PROJECT SUMMARY Skin cancer, already the most common cancer in the U.S., is increasing dramatically in incidence due to the combined effects recreational sun exposure and the aging of the U.S. population. This proposal will apply powerful genome-wide epigenetic techniques to human patient samples and in vitro and in vivo models to determine how alterations in the skin epigenome drive cutaneous carcinogenesis, and identify chromatin modifiers that may be targeted for prevention and treatment. By focusing on the role of epigenomic dysregulation in the promotion of keratinocyte cancers, this project directly engages the Keratinocyte Biology and Diseases Program at NIAMS, and specifically addresses the goals of the NIAMS 2015-2019 Long-Range Plan, including the investigation of chromatin structure and epigenetic mechanisms in the skin. Candidate: Brian Capell received his M.D. and Ph.D. from New York University in 2009. In 2013, he was board-certified following the completion the Dermatology Residency Program at the University of Pennsylvania. He is currently an Instructor and Postdoctoral Fellow in the Dermatology Department and Epigenetics Program at Penn, pursuing training in a laboratory dedicated to understanding epigenetic mechanisms involved in cancer and aging. This proposal builds upon his established interest in cellular senescence and genetics, will produce novel scientific results, and additionally provide critical training to the candidate. The applicant's long-term goal is to become a R01-funded independent investigator studying how epigenetic mechanisms contribute to skin diseases. Environment: Dr. Capell's mentor, Dr. Shelley Berger, provides unparalleled expertise. Dr. Berger is world-renowned for her research on epigenetics and chromatin structure and function in genomic regulation. She has been continuously funded by NIH throughout her career and offers extensive resources for the work described in this proposal. Dr. Berger also has a robust track record of mentorship. The applicant's career development plan entails rigorous training in epigenetic techniques and computational biology, including coursework in these areas crucial to his success, and close guidance from a diverse and dedicated network of scientific advisors. In addition, Dr. Capell has the full support of the Department of Dermatology at Penn. Research: Dr. Capell's preliminary results show that inflammation during cellular senescence, known as the senescence-associated secretory phenotype (SASP), can be attenuated by novel epigenetic drugs. This occurs through abrogation of DNA damage response activation and direct modification of the local chromatin environment over SASP genes. How the epigenome may be altered and drive skin carcinogenesis is poorly understood. As recent studies have demonstrated that genetic mutations alone are insufficient for the development of skin cancer, the investigators hypothesize that an understanding of epigenetic processes during the earliest stages of skin carcinogenesis may provide novel opportunities for prevention and therapy. This proposal will build on Dr. Capell's preliminary data to 1) define the global epigenomic and transcriptional alterations that occur during skin photoaging and carcinogenesis, and 2) identify chromatin regulators that can be targeted to prevent UV-induced epigenomic alterations and carcinogenic transformation. The proposed scientific inquiry, Dr. Berger's mentorship, and the enthusiastic support of the candidate's Department and advisory committee will enable Dr. Capell to launch a successful career as an independent physician-scientist.