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

描述(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。黑素细胞是产生色素的细胞，其恶变会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。在造成黑色素瘤的环境因素中，暴露在太阳紫外线辐射下是黑色素瘤发生的主要风险因素，作为启动者，导致重要的黑色素瘤癌基因/肿瘤抑制基因突变，而紫外线辐射也通过免疫系统调节，如晒伤介导的炎症和免疫抑制，起到促进作用。在人类和胎盘动物中，核苷酸切除修复(NER)可以消除UVR引起的基因损伤，UVR会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小时昼夜循环一起，在多种生理和生化过程中构成每日节律的基础。最近，我发现NER途径的关键成分XPA蛋白的水平和NER的比率在小鼠皮肤中都是按昼夜节律振荡的。重要的是，我发现早上接受UVR照射的小鼠比晚上接受UVR照射的小鼠更容易患上鳞状细胞癌，因为UVR的修复率很低。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还没有被探索。这样的研究是必要的，因为NER是一种预防UVR诱导的黑色素瘤的防御机制，受生物钟控制。因此，本项目将使用转基因小鼠模型和从这些模型衍生的原代黑素细胞来了解生物钟在黑素细胞生物学中的作用(目标1，K99期)，确定生物钟在UVR诱导的黑素细胞增殖和晒伤/炎症过程中的功能(目标2，K99和R00期)，并确定DNA损伤反应信号通路和环境黑色素瘤发生作为生物钟的功能(目标3，R00期)。所获得的信息将用于测试是否可以利用黑素细胞生物学的昼夜节律效应来防止紫外线诱导的黑色素瘤发生。

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.