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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.

生物钟紊乱：环境致癌的一个危险因素