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

描述：本研究项目的目的是调查生物钟在黑素细胞中的作用 生物学和太阳紫外线辐射（UVR）诱导的黑色素瘤。恶性转化 黑素细胞、产生色素的细胞导致黑色素瘤的发展。皮肤黑色素瘤 最致命的皮肤癌，也是美国增长最快的癌症之一。 环境因素，暴露于太阳紫外线辐射是黑色素瘤发展的主要危险因素， 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，UVR也作为 启动子，通过免疫系统调节，如晒伤介导的炎症， 免疫抑制在人类和有胎盘动物中，核苷酸切除修复（NER）可以去除遗传物质。 紫外线辐射造成的伤害，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，是多种生理和生物化学的日常节律的基础。 与24小时昼夜循环一致。最近，我发现XPA蛋白的水平， 在小鼠皮肤中，NER途径的组成部分和NER的速率都以昼夜节律振荡。 重要的是，我发现在早晨接受紫外线辐射的小鼠，当修复率较低时， 比晚上照射的小鼠更容易发生鳞状细胞癌。然而，影响 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研究。等 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， 由生物钟控制。因此，本项目将使用转基因小鼠模型， 从这些模型中获得的原代黑素细胞，以了解生物钟在黑素细胞中的作用。 生物学（Aim 1，K99期），鉴定UVR诱导的黑素细胞增殖中的生物钟功能， 晒伤/炎症过程（Aim 2，K99和R 00阶段），并鉴定DNA损伤反应信号传导 途径和环境黑色素瘤作为昼夜节律钟的功能（Aim 3，R 00阶段）。的 所获得的信息将用于测试是否可以利用对黑素细胞生物学的昼夜节律效应， 防止紫外线诱发的黑色素瘤。

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.