Circadian clock disruption: A risk factor for environmental carcinogenesis

昼夜节律紊乱：环境致癌的危险因素

基本信息

批准号：
9883425
负责人：
Shobhan Gaddameedhi
金额：
$ 49.87万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-17 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883425
关键词：
Acute Address Affect American Biological Process Carcinogenesis Mechanism Carcinogens Cell Cycle Checkpoint Cells Chronic Circadian Dysregulation Circadian Rhythms Critical Pathways Cues DNA Damage DNA Repair Data Development Disease Disease Outcome Disease Progression Ensure Environmental Impact Environmental Risk Factor Epidemiology Event Experimental Models Exposure to Fibroblasts Frequencies Gene Expression Genes Genetic Genome Genome Stability Genomic Instability Genotoxic Stress Health Hour Human Impairment In Vitro Inbred HRS Mice Incidence Individual Induced Mutation Inflammation Inflammatory Inflammatory Response Intervention Knowledge Lead Light Maintenance Malignant - descriptor Malignant Neoplasms Mediating Mission Molecular Mus National Institute of Environmental Health Sciences Nucleotide Excision Repair OGG1 gene Outcome Outcome Study Pathway interactions Periodicity Phase Predisposition Prevention Prevention strategy Preventive Intervention Process Punch Biopsy Radiation Regulation Research Risk Risk Factors Role Sampling Severity of illness Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Neoplasms Sleep disturbances Study models Testing Time UV protection UVB induced Ultraviolet B Radiation Work XPA gene base cancer initiation cancer risk cancer type carcinogenesis carcinogenicity circadian circadian pacemaker disorder prevention environmental carcinogenesis environmental mutagens epidemiology study experimental study human subject improved in vivo in vivo Model insight lifestyle factors mouse model novel patient population preservation response shift work skin disorder tumor tumor progression ultraviolet virtual

项目摘要

Circadian clock disruption: A risk factor for environmental carcinogenesis Abstract/Summary Circadian clocks respond to environmental time cues to coordinate 24-hour rhythmicity in gene expression and biological processes in virtually all cells of the body. According to the US Department of Labor, ~15-20% of Americans are engaged in rotating shift work, and the resulting altered timing of wake/sleep disrupts their endogenous circadian clock. Epidemiological studies have concluded that individuals who perform long-term rotating shift work suffer from an increased risk of several cancer types, including skin cancers. Skin cancer is the most common malignancy and its incidence is increasing dramatically in the U.S. Among the contributing factors, exposure to solar ultraviolet B (UVB) radiation is the major risk factor (up to 90%) for malignant transformation of skin cells and skin cancer development. In humans and mice, nucleotide excision repair (NER) removes genetic damage caused by UVB. Therefore, protection from UVB exposure and ensuring efficient NER capacity are critical for maintenance of genomic stability and prevention of skin cancer. Previous studies using genetic mouse models have shown that the circadian clock regulates several tumor suppressing pathways, including NER, that are critical for preserving genomic stability and protection against environmental carcinogenesis. However, there is a fundamental gap in understanding how circadian disruption associated with rotating shift work leads to environmental carcinogenesis and in the underlying molecular mechanisms that influence disease progression in humans. This lack of knowledge is an important roadblock because it highlights the need for mechanistic insight into malignant transformation and represents a barrier to predicting the severity of disease outcomes in shift workers. The overall objectives of this project are to identify and characterize early stage carcinogenesis mechanisms and consequences of circadian disruption in UVB- induced skin carcinogenesis. Our central hypothesis, supported by preliminary data, is that circadian disruption undermines DNA repair capacity, inflammatory responses, and other genotoxic stress-related cellular pathways that underlie the carcinogenicity of shift work. Our studies use circadian synchronized skin cells in vitro, circadian-disrupted and skin carcinogenesis-prone SKH-1 genetic mouse models in vivo, and skin samples from human subjects in vivo. In Aim 1, we will determine how the circadian rhythm impacts solar UVB radiation-mediated DNA damage responses including DNA repair and inflammatory responses. The experiments described in Aim 2 will examine how clock disruption by rotating shift work influences circadian rhythmicity and NER. In Aim 3, we will characterize how rotating shift work and genetic disruption of the circadian clock influence skin cancer initiation and progression. Collectively, the outcomes from these studies will provide a molecular roadmap of circadian disruption in UVB radiation-mediated genomic instability and carcinogenesis and will lead to the identification of novel mechanisms that can be applied toward disease prevention in individuals with abnormal circadian function.

昼夜节律破坏：环境致癌的危险因素摘要/摘要昼夜节律响应环境时间提示，以协调基因24小时的节奏性几乎所有细胞的表达和生物过程。根据美国劳工部的说法〜15-20％的美国人从事旋转的轮班工作，由此产生的唤醒/睡眠时间改变了破坏他们的内源性昼夜节律。流行病学研究得出的结论是，进行长期旋转转移工作的遭受多种癌症类型的风险增加，包括皮肤癌症。皮肤癌是最常见的恶性肿瘤，其发病率在美国急剧增加在促成因素中，暴露于太阳能紫外线B（UVB）辐射是主要危险因素（最多 90％）用于皮肤细胞和皮肤癌发育的恶性转化。在人类和小鼠中，核苷酸切除修复（NER）消除了UVB引起的遗传损害。因此，防止UVB暴露和确保有效的NER容量对于维持基因组稳定性和预防皮肤癌至关重要。先前使用遗传小鼠模型的研究表明，昼夜节律调节了几个肿瘤抑制包括NER在内的途径，这对于保留基因组稳定性和保护至关重要环境致癌作用。但是，了解昼夜节律的干扰存在根本的差距与旋转的工作相关的是环境癌变和基础分子影响人类疾病进展的机制。缺乏知识是一个重要的障碍因为它强调了对恶性转化的机械洞察的需求，并代表了预测转移工人中疾病结局的严重程度。该项目的总体目标是确定并表征了早期癌变机制和昼夜节律破坏UVB-的后果诱导皮肤致癌。我们的中心假设在初步数据的支持下是昼夜节律的破坏破坏DNA修复能力，炎症反应和其他与遗传毒性相关的细胞转移工作的致癌性的途径。我们的研究使用昼夜节律的皮肤细胞体内的体外，昼夜节律破坏和皮肤致癌的体内遗传小鼠模型和皮肤体内人类受试者的样本。在AIM 1中，我们将确定昼夜节律如何影响太阳UVB 辐射介导的DNA损伤反应，包括DNA修复和炎症反应。这 AIM 2中描述的实验将检查如何通过旋转移动工作来影响时钟的破坏会影响昼夜节律节奏和ner。在AIM 3中，我们将表征旋转转移的工作和遗传破坏昼夜节律会影响皮肤癌的启动和进展。总的来说，这些研究的结果将在UVB辐射介导的基因组不稳定性中提供昼夜节律中断的分子路线图和致癌作用，并将导致鉴定可以应用于疾病的新机制昼夜节律异常功能的个体的预防。