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: 8730654
• 负责人: Shobhan Gaddameedhi
• 金额: $ 8.64万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730654
• 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; 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; p19ARF; prevent; promoter; public health relevance; repaired; response; transcription factor; xeroderma pigmentosum group A complementing protein

DESCRIPTION (provided by applicant): 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（由申请人提供）：该研究项目的目的是研究昼夜节律时钟在黑素细胞生物学和太阳紫外线辐射（UVR）引起的黑素作用中的作用。黑色素细胞的恶性转化，产生色素细胞，导致黑色素瘤的发展。 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免疫抑制。在人类和胎盘动物中，核苷酸切除修复（NER）消除了由UVR引起的遗传损害，导致黑色素瘤和非黑色素瘤皮肤癌。昼夜节律时钟是分子时间保存系统，它是与24小时夜间周期共同进行多种生理和生化过程中每日节奏的基础。最近，我发现XPA蛋白的水平是NER途径的关键组成部分和NER的速率，均以小鼠皮肤中的昼夜节律振荡。重要的是，我发现早晨用UVR辐照的小鼠在维修率较低时更容易受到鳞状细胞癌的发育，而不是晚上辐照的小鼠。然而，尚未探索昼夜节律时钟对黑色素细胞生物学和UVR诱导的黑色素瘤的影响。需要此类研究，因为NER是一种防止UVR引起的黑色素瘤的防御机制，受昼夜节律控制。 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黑色素作用是昼夜节律时钟的函数（AIM 3，R00相）。获得的信息将用于测试昼夜节律对黑素细胞生物学的影响，以防止UVR诱导的黑色素作仿。