Circadian clock disruption: A risk factor for environmental carcinogenesis

昼夜节律紊乱：环境致癌的危险因素

• 批准号: 10297865
• 负责人: Shobhan Gaddameedhi
• 金额: $ 40万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-28 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297865
• 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; 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; preventive intervention; response; shift work; skin disorder; solar ultraviolet radiation; tumor; tumor progression; ultraviolet; virtual

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.

昼夜节律紊乱：环境致癌的危险因素 摘要/总结 生物钟响应环境时间线索来协调基因的 24 小时节律 身体几乎所有细胞的表达和生物过程。据美国劳工部称， 约 15-20% 的美国人从事轮班工作，从而改变起床/睡眠时间 扰乱他们的内源性生物钟。流行病学研究得出的结论是，以下人群 长期轮班工作会增加患多种癌症（包括皮肤癌）的风险 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，暴露于太阳紫外线 B (UVB) 辐射是主要风险因素（高达 90%）用于皮肤细胞的恶性转化和皮肤癌的发展。在人类和小鼠中，核苷酸 切除修复 (NER) 可消除 UVB 造成的遗传损伤。因此，防止 UVB 暴露和 确保高效的 NER 能力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，生物钟调节多种肿瘤 抑制途径，包括 NER，对于保持基因组稳定性和防止病毒感染至关重要 环境致癌。然而，在理解昼夜节律如何被破坏方面存在着根本性的差距。 与轮班工作相关的导致环境致癌和潜在的分子致癌 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进行机械洞察的必要性，并且代表了恶性转化的障碍 预测轮班工人疾病结果的严重程度。该项目的总体目标是确定 并描述早期致癌机制和 UVB-昼夜节律破坏的后果 诱发皮肤癌。我们的中心假设（得到初步数据的支持）是昼夜节律紊乱 破坏 DNA 修复能力、炎症反应和其他与基因毒性应激相关的细胞 轮班工作致癌的途径。我们的研究使用昼夜节律同步的皮肤细胞 体外、昼夜节律紊乱和皮肤致癌倾向的 SKH-1 遗传小鼠模型体内和皮肤 来自人类受试者体内的样本。在目标 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 目标 2 中描述的实验将研究轮班工作造成的时钟干扰如何影响昼夜节律 节奏性和NER。在目标 3 中，我们将描述轮班工作和遗传破坏的特征 生物钟影响皮肤癌的发生和进展。总的来说，这些研究的结果 将提供 UVB 辐射介导的基因组不稳定性中昼夜节律破坏的分子路线图 致癌作用并将导致识别可应用于疾病的新机制 昼夜节律功能异常的个体的预防。