Epigenomic mechanisms of skin carcinogenesis

项目摘要 皮肤癌已经是美国最常见的癌症，发病率急剧上升， 休闲阳光照射和美国人口老龄化的综合影响。这项建议会 将强大的全基因组表观遗传技术应用于人类患者样本以及体外和体内模型 以确定皮肤表观基因组的改变如何驱动皮肤癌的发生，并确定染色质 可以作为预防和治疗的靶向修饰剂。通过关注表观基因组的作用 在促进角质形成细胞癌症的失调，这个项目直接从事角质形成细胞生物学 和疾病计划在NIAMS，并具体解决了NIAMS 2015-2019年长期目标 计划，包括染色质结构和皮肤表观遗传机制的调查。候选人： 布莱恩·卡佩尔获得了医学博士学位。和博士2009年从纽约大学毕业2013年，他获得了董事会认证， 在宾夕法尼亚大学完成皮肤科住院医师课程后。现任 宾夕法尼亚大学皮肤科和表观遗传学项目的讲师和博士后研究员， 在致力于了解癌症所涉及的表观遗传机制的实验室进行培训， 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，并额外提供关键的培训，以候选人。申请人的长期目标 是成为R 01资助的独立调查员，研究表观遗传机制如何对皮肤产生影响。 疾病环境：Capell博士的导师Shelley Berger博士提供了无与伦比的专业知识。伯杰博士是 她在表观遗传学和染色质结构和基因组调控功能方面的研究享誉世界。 她在整个职业生涯中一直得到NIH的资助，并为这项工作提供了广泛的资源。 在这个提案中描述。伯杰博士也有一个强大的指导记录。申请人的职业 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 这些领域的课程对他的成功至关重要，并从一个多样化和专门的网络密切指导， 科学顾问。此外，Capell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表明，细胞衰老过程中的炎症，即所谓的 衰老相关的分泌表型（SASP），可以减弱新的表观遗传药物。这 通过消除DNA损伤反应激活和直接修饰局部染色质而发生 环境对SASP基因的影响。表观基因组如何被改变并驱动皮肤癌发生尚不清楚。 明白最近的研究表明，单靠基因突变不足以使 皮肤癌的发展，研究人员假设，对表观遗传过程的理解 在皮肤癌发生的最早阶段，可能为预防和治疗提供新的机会。 该提案将建立在Capell博士的初步数据基础上，以1）定义全球表观基因组和转录 在皮肤光老化和癌变过程中发生的变化，以及2）识别染色质调节剂， 有针对性地防止紫外线诱导的表观基因组改变和致癌转化。拟议 伯杰博士的指导，以及候选人所在部门的热情支持， 咨询委员会将使卡佩尔博士能够作为一名独立的医生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.