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Epigenomic mechanisms of skin carcinogenesis

皮肤癌发生的表观基因组机制

基本信息

批准号：
9506701
负责人：
Brian Capell
金额：
$ 14.72万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9506701
关键词：
ATAC-seq Acetylation Address Advisory Committees Affect Aging American Area Attenuated Automobile Driving Biological Assay Biology CRISPR/Cas technology Cell Aging Cells ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Chronic Clinical Computational Biology Coupled Cutaneous DNA DNA Damage DNA Sequence Alteration Data Dermatology Development Development Plans Disease Doctor of Medicine Doctor of Philosophy Environment Environmental Risk Factor Enzymes Epidemic Epigenetic Process Fibroblasts Funding Gene Expression Gene Expression Alteration Genes Genetic Genetic Transcription Genomics Goals Grant Growth Histones Human IL8 gene In Vitro Incidence Inflammation Inflammatory Interstitial Collagenase Investigation Laboratories Lead Link MLL gene Malignant Neoplasms Mentors Mentorship Modification Mutation National Institute of Arthritis and Musculoskeletal and Skin Diseases New York Oncogenes Oncogenic Pathway interactions Patients Pennsylvania Pharmacology Phenotype Physicians Play Population Positioning Attribute Postdoctoral Fellow Prevention Prevention therapy Regulation Research Research Personnel Residencies Resources Role Sampling Scientific Inquiry Scientist Skin Skin Aging Skin Cancer Skin Carcinogenesis Stress Sun Exposure Techniques Test Result The Sun Therapeutic Intervention Time Training Transcription Alteration UV Radiation Exposure UV induced Ultraviolet Rays United States National Institutes of Health Universities Variant Work Writing base carcinogenesis carcinogenicity career career development cost cytokine epigenetic drug epigenetic therapy epigenome epigenomics genome-wide high throughput screening histone methylation histone modification human model in vivo in vivo Model in vivo evaluation inhibitor/antagonist instructor interest keratinocyte mouse model novel prevent programs response senescence skin cancer prevention skin disorder skin organogenesis skin squamous cell carcinoma small hairpin RNA success therapeutic target transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis

项目摘要

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.

项目总结