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Epigenetic regulation of radiation damage in oral mucosa

口腔粘膜辐射损伤的表观遗传调控

基本信息

批准号：
9005855
负责人：
WEI CHEN
金额：
$ 11.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-05 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005855
关键词：
Adherent Culture American CDKN2A gene Cell Death Cell Proliferation Cells Disease EZH2 gene Epigenetic Process Epithelium Equilibrium Exposure to Foundations Future Gene Expression Genes Goals Growth Head and Neck Cancer Head and neck structure Health Histones Human In Situ In Vitro Inflammation Inflammatory Interleukin-6 Interleukin-8 Interleukins Intraperitoneal Injections Investigation Ionizing radiation Knockout Mice Lead Lysine Mediating Methyltransferase Modeling Mucositis Mus NF-kappa B Normal Cell Normal tissue morphology Oral Oral cavity Oral mucous membrane structure Outcome Oxidases PRC1 Protein Pain Pathogenesis Patients Peptide Hydrolases Phase Phenotype Polycomb Process Production Promoter Regions Property Proteins RNA Interference Radiation Radiation therapy Radioprotection Reaction Research Role Signal Pathway TNF gene Testing Therapeutic Tissues Tongue Transduction Gene Ulcer chromatin immunoprecipitation cytokine effective therapy epigenetic regulation gain of function histone demethylase histone methyltransferase histone modification in vivo inhibitor/antagonist irradiation keratinocyte mouse model novel novel therapeutics oral lesion oral mucositis overexpression premature programs radiation response regenerative research study response secretory protein senescence vector

项目摘要

DESCRIPTION (provided by applicant): The purpose of this application is to investigate a novel mechanism regulating cellular responses to ionizing radiation (IR) in oral mucosa and to develop effective therapies for treating radiation damage in oral cavity. Exposure to ionizing radiation causes damage to oral mucosa that culminates in oral mucositis, a painful and debilitating disorder highly prevalent in patients receiving radiation therapy for head and neck cancer. IR triggers the onset of radiation-induced premature senescence (RIPS) that mediates tissue damage. Senescent cells secrete growth factors, proteases, and pro-inflammatory cytokines, through a process called senescence- associated secretory phenotype (SASP), which may contribute to the inflammatory phase of oral mucositis in irradiated tissues. At the mechanistic level, we recently found that IR exposure induces premature senescence in normal human oral keratinocytes (NHOK) through epigenetic mechanism that involves activation of histone demethylase, e.g., Jmjd3, loss of polycomb group (PcG) proteins, e.g., Bmi-1 and EZH2, and altered level of trimethylated histone H3K27 (H3K27me3), indicating that normal cell radiation response is in part determined through the balance between Jmjd3 and PcG proteins. When we perturbed the balance between Jmjd3 and PcG by overexpression of Bmi-1, we found that RIPS was strongly inhibited in cells and the global level of H3K27me3 was maintained even after IR exposure. Such radioprotective effects of Bmi-1 overexpression were observed in monolayer culture of NHK, as well as in organotypic raft culture in 3D. Taken together, these results raise a hypothesis that epigenetic changes by the interplay between Jmjd3 and the PcG proteins mediate the onset of RIPS and SASP upon radiation exposure. This hypothesis will be tested by investigating the roles of Jmjd3 and PcG proteins in epigenetic regulation of RIPS and SASP in NHOK in response to IR; determining the occurrence of RIPS and the corresponding epigenetic changes in oral mucosa after exposure to IR in vivo; and determining the effects of altered Jmjd3 or PcG status on RIPS in oral mucosa exposed to radiation. These experiments will elucidate a novel epigenetic mechanism underlying radiation- induced oral mucositis, and lay the foundation for developing novel therapeutics for oral mucositis in future research.

描述（由申请人提供）：本申请的目的是研究调节口腔粘膜中电离辐射（IR）细胞反应的新机制，并开发治疗口腔辐射损伤的有效疗法。暴露于电离辐射会对口腔粘膜造成损害，最终导致口腔粘膜炎，这是一种痛苦且使人衰弱的疾病，在接受头颈癌放射治疗的患者中非常普遍。红外线会引发辐射引起的早衰 (RIPS)，从而介导组织损伤。衰老细胞通过称为衰老相关分泌表型（SASP）的过程分泌生长因子、蛋白酶和促炎细胞因子，这可能导致受辐射组织中口腔粘膜炎的炎症阶段。在机制层面上，我们最近发现红外线暴露通过表观遗传机制诱导正常人口腔角质形成细胞（NHOK）过早衰老，该机制涉及组蛋白去甲基化酶（例如 Jmjd3）的激活、多梳族（PcG）蛋白（例如 Bmi-1 和 EZH2）的丢失以及三甲基化组蛋白 H3K27 水平的改变 (H3K27me3)，表明正常细胞辐射反应部分是通过 Jmjd3 和 PcG 蛋白之间的平衡决定的。当我们通过 Bmi-1 的过度表达扰乱 Jmjd3 和 PcG 之间的平衡时，我们发现细胞中的 RIPS 受到强烈抑制，并且即使在红外线照射后，H3K27me3 的整体水平仍保持不变。 Bmi-1 过表达的这种辐射防护作用在 NHK 的单层培养物以及 3D 器官型筏培养物中观察到。综上所述，这些结果提出了一个假设：Jmjd3 和 PcG 蛋白之间的相互作用导致的表观遗传变化介导了辐射暴露后 RIPS 和 SASP 的发生。该假设将通过研究 Jmjd3 和 PcG 蛋白在 NHOK 响应 IR 的 RIPS 和 SASP 表观遗传调控中的作用来检验；确定体内暴露于IR后口腔粘膜中RIPS的发生以及相应的表观遗传变化；并确定 Jmjd3 或 PcG 状态改变对暴露于辐射的口腔粘膜 RIPS 的影响。这些实验将阐明辐射诱发口腔粘膜炎的新表观遗传机制，并为未来研究开发口腔粘膜炎新疗法奠定基础。