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

描述（由申请人提供）：本研究项目的目的是研究生物钟在黑素细胞生物学和太阳紫外线辐射（UVR）诱导的黑色素瘤形成中的作用。黑色素细胞的恶性转化，产生色素的细胞，导致黑色素瘤的发展。皮肤黑色素瘤是最致命的皮肤癌形式，也是美国增长最快的癌症之一。在环境因素中，暴露于太阳紫外线辐射是黑色素瘤发展的主要危险因素，它作为引发者，引起重要的黑色素瘤致癌基因/肿瘤抑制因子的突变，紫外线辐射也作为促进者，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）可以去除紫外线照射引起的遗传损伤，这种损伤会导致黑色素瘤和非黑色素瘤皮肤癌。昼夜节律钟是一种分子计时系统，它是多种生理和生化过程中与24小时昼夜周期一致的日常节律的基础。最近，我发现XPA蛋白（NER通路的关键成分）的水平和NER的速率在小鼠皮肤中都随着昼夜节律而波动。重要的是，我发现在早上接受UVR照射的小鼠，当修复率较低时，比晚上接受UVR照射的小鼠更容易发生鳞状细胞癌。然而，生物钟对黑素细胞生物学和uvr诱导的黑色素瘤的影响尚未被探索。这种研究是必要的，因为黑色素瘤是一种防御机制，可以防止紫外线辐射引起的黑色素瘤，它是由生物钟控制的。因此，本项目将使用转基因小鼠模型和源自这些模型的原代黑素细胞来了解生物钟在黑素细胞生物学（Aim 1， K99期）中的作用，确定生物钟在uvr诱导的黑素细胞增殖和晒伤/炎症过程（Aim 2， K99和R00期）中的功能，并确定DNA损伤反应信号通路和环境黑素瘤形成作为生物钟的功能（Aim 3， R00期）。获得的信息将用于测试是否可以利用昼夜节律对黑素细胞生物学的影响来预防uvr诱导的黑色素瘤形成。

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.