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

描述（由申请人提供）：本研究项目的目标是研究生物钟在黑素细胞生物学和太阳紫外线辐射（UVR）诱导的黑色素瘤发生中的作用。黑素细胞（产生色素的细胞）的恶性转化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。在促成环境因素中，暴露于太阳紫外线辐射是黑色素瘤发展的主要风险因素，作为引发剂，导致重要的黑色素瘤致癌基因/肿瘤抑制因子突变，紫外线也通过免疫系统调节（如晒伤介导的炎症和免疫抑制）作为促进剂。在人类和胎盘动物中，核苷酸切除修复（NER）消除了由UVR引起的遗传损伤，导致黑色素瘤和非黑色素瘤皮肤癌。生物钟是一种分子计时系统，它与24小时昼夜循环相一致，是多种生理和生化过程中每日节律的基础。最近，我发现XPA蛋白（NER途径的关键成分）的水平和NER的速率都随小鼠皮肤的昼夜节律振荡。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紫外线诱导的黑色素瘤的影响尚未探讨。这类研究是必要的，因为NER是一种防御机制，可以防止紫外线诱导的黑色素瘤，是由生物钟控制的。因此，本计画将使用基因改造的鼠类模型及从这些模型衍生的原代黑素细胞，以了解生物钟在黑素细胞生物学上的角色（目的1，K99期），鉴定UVR诱导的黑素细胞增殖和晒伤/炎症过程中的生物钟功能（Aim 2，K99和R 00阶段），并确定DNA损伤反应信号传导途径和环境黑色素瘤作为生物钟的功能（Aim 3，R 00阶段）。所获得的信息将被用来测试是否昼夜节律对黑素细胞生物学的影响，可以利用，以防止紫外线诱导的黑色素瘤。

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.