Role of the circadian clock in melanocyte biology and UV-induced melanomagenesis

生物钟在黑色素细胞生物学和紫外线诱导的黑色素瘤发生中的作用

• 批准号: 8989534
• 负责人: Shobhan Gaddameedhi
• 金额: $ 24.9万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989534
• 关键词: American Cancer Society; Anabolism; Animals; Apoptosis; Applications Grants; Biochemical Process; Biology; Cancer Etiology; Cells; Cessation of life; Circadian Rhythms; Collaborations; Complex; Cutaneous Melanoma; DNA Damage; DNA photoproducts; Data; Defense Mechanisms; Development; Diagnosis; Disease; Environmental Risk Factor; Erythema; Etiology; Exposure to; Fluorescence; Foundations; Genes; Genetic; Genetic Models; Goals; Human; Immune system; Immunohistochemistry; Immunosuppression; Incidence; Inflammation; Inflammatory; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Melanins; Modeling; Molecular; Mus; Mutation; Nucleotide Excision Repair; Outcome; PTEN gene; Pathway interactions; Periodicity; Phase; Physiological Processes; Pigments; Play; Prevention; Prevention strategy; Process; Proteins; Radiation Induced DNA Damage; Regulation; Research Personnel; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Squamous cell carcinoma; Sunburn; System; TP53 gene; Testing; Therapeutic; Time; Tumor Suppressor Genes; UV induced; Ultraviolet Radiation Biology; Ultraviolet Rays; United States; Variant; Work; XPA gene; base; circadian pacemaker; disorder prevention; human tissue; innovation; melanocyte; melanoma; mouse model; p19ARF; prevent; promoter; repaired; response; transcription factor; xeroderma pigmentosum group A complementing protein

DESCRIPTION: The goal of this research project is to investigate the role of the circadian clock in melanocyte biology and solar ultraviolet radiation (UVR)-induced melanomagenesis. The malignant transformation of melanocytes, pigment producing cells, leads to the development of melanoma. Cutaneous melanoma is the deadliest form of skin cancer and one of the fastest growing cancers in the U.S. Among the contributing environmental factors, exposure to solar UV radiation is a major risk factor for melanoma development, acting as an initiator, causing mutations in important melanoma oncogenes/tumor-suppressors, and UVR also acts as a promoter, through immune system modulation such as sunburn-mediated inflammation and immunosuppression. In human and placental animals, nucleotide excision repair (NER) removes genetic damage caused by UVR which causes melanoma and non-melanoma skin cancer. The circadian clock is the molecular time-keeping system that underlies daily rhythms in multiple physiological and biochemical processes in concert with the 24 h day-night cycle. Recently, I found that the level of the XPA protein, a key component of the NER pathway, and the rate of NER, both oscillate with a circadian rhythm in mouse skin. Importantly, I found that mice irradiated with UVR in the morning, when the repair rate was low, were more susceptible to development of squamous cell carcinoma than mice irradiated in the evening. However, effects of the circadian clock on melanocyte biology and UVR-induced melanoma have not been explored. Such studies are needed because NER, which is a defense mechanism that prevents UVR-induced melanoma, is controlled by the circadian clock. Therefore, this project will use genetically modified murine models and primary melanocytes derived from those models to understand the role of the circadian clock in melanocyte biology (Aim 1, K99 phase), identify the circadian clock function in UVR-induced melanocyte proliferation and sunburn/inflammatory processes (Aim 2, K99 and R00 phases), and identify DNA damage response signaling pathways and environmental melanomagenesis as a function of the circadian clock (Aim 3, R00 phase). The information obtained will be used to test whether circadian effects on melanocyte biology can be exploited to prevent UVR-induced melanomagenesis.

描述：该研究项目的目标是研究生物钟在黑素细胞中的作用。 生物学和太阳紫外线(UVR)诱导的黑色素瘤发生。人的恶性转化 黑素细胞是产生色素的细胞，会导致黑色素瘤的发展。皮肤黑色素瘤是 最致命的皮肤癌，也是美国增长最快的癌症之一。 环境因素，暴露在太阳紫外线辐射下是黑色素瘤发生的主要危险因素， 作为启动者，导致重要的黑色素瘤癌基因/肿瘤抑制基因的突变，而紫外线辐射也起到了 启动子，通过免疫系统调节，如晒伤介导的炎症和 免疫抑制。在人类和胎盘动物中，核苷酸切除修复(NER)移除了基因 紫外线照射会导致黑色素瘤和非黑色素瘤皮肤癌。昼夜节律时钟是 多种生理生化中构成日常节律的分子计时系统 与24小时昼夜循环相一致的过程。最近，我发现XPA蛋白的水平是一个关键 NER途径的成分和NER的速率在小鼠皮肤中都以昼夜节律振荡。 重要的是，我发现早上接受UVR照射的小鼠，当修复率较低时，小鼠 比傍晚照射的小鼠更容易发生鳞状细胞癌。然而，效果 生物钟对黑素细胞生物学和紫外线诱导的黑色素瘤的影响还没有被探索。是这样的 之所以需要研究，是因为NER是一种预防UVR诱导的黑色素瘤的防御机制 由生物钟控制。因此，该项目将使用转基因小鼠模型和 从这些模型中获得原代黑素细胞以了解生物钟在黑素细胞中的作用 生物学(目标1，K99期)，确定UVR诱导的黑素细胞增殖中的昼夜节律功能 晒伤/炎症过程(目标2、K99和R00阶段)，并识别DNA损伤反应信号 作为生物钟功能的途径和环境黑色素瘤的发生(目标3，R00阶段)。这个 所获得的信息将被用于测试黑素细胞生物学的昼夜节律效应是否可以被利用 防止紫外线诱导的黑色素瘤发生。