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

基本信息

批准号：
9198219
负责人：
Shobhan Gaddameedhi
金额：
$ 24.9万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198219
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 Foundations Genes Genetic Genetic Models Goals Human Immune system Immunoblot Analysis Immunofluorescence Immunologic Immunohistochemistry Immunosuppression Incidence Inflammation Inflammatory 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 TP53 gene Testing Therapeutic Time Tumor Suppressor Genes UV induced Ultraviolet Rays United States Variant Work XPA gene base circadian pacemaker disorder prevention human tissue innovation melanocyte melanoma mouse model p19ARF prevent promoter repaired response transcription factor xeroderma pigmentosum group A complementing protein

项目摘要

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.

描述：该研究项目的目的是研究昼夜节律在黑色素细胞中的作用生物学和太阳能紫外线辐射（UVR）诱导的黑色素作用。恶性转变黑色素细胞，色素产生细胞，导致黑色素瘤的发展。皮肤黑色素瘤是皮肤癌最致命的形式，是美国增长最快的癌症之一环境因素，暴露于太阳能紫外线辐射是黑色素瘤发育的主要危险因素，作用作为引发剂，引起重要的黑色素瘤癌基因/肿瘤抑制剂的突变，UVR也充当启动子，通过免疫系统调节，例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）去除遗传 UVR造成的损害会导致黑色素瘤和非黑色素瘤皮肤癌。昼夜钟是分子时间保存系统，该系统是多种生理和生化的每日节奏的基础与24小时的昼夜周期一致的过程。最近，我发现XPA蛋白的水平是钥匙 NER途径的成分和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照射的小鼠在维修率较低时，更多比晚上辐照的小鼠易受鳞状细胞癌的发育。但是，效果尚未探讨昼夜节律生物学和UVR诱导的黑色素瘤的时钟。这样的需要研究，因为NER是一种防止UVR引起的黑色素瘤的防御机制，是由昼夜节律控制。因此，该项目将使用转基因的鼠模型和从这些模型中得出的主要黑素细胞，以了解昼夜节律在黑色素细胞中的作用生物学（AIM 1，K99期），确定UVR诱导的黑素细胞增殖中的昼夜节律函数晒伤/炎症过程（AIM 2，K99和R00阶段），并识别DNA损伤响应信号传导途径和环境黑色素作用是昼夜节律的函数（AIM 3，R00相）。这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是否可以利用为预防UVR诱导的黑色素作用。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock.

DOI：
10.1101/gad.249417.114
发表时间：
2014-09-15
期刊：
Genes & development
影响因子：
10.5
作者：
Ye R;Selby CP;Chiou YY;Ozkan-Dagliyan I;Gaddameedhi S;Sancar A
通讯作者：
Sancar A

Impact of the Circadian Clock on UV-Induced DNA Damage Response and Photocarcinogenesis.

DOI：
10.1111/php.12662
发表时间：
2017-01
期刊：
Photochemistry and photobiology
影响因子：
3.3
作者：
Dakup P;Gaddameedhi S
通讯作者：
Gaddameedhi S

Cardiac autonomic activity during simulated shift work.

DOI：
10.2486/indhealth.2018-0044
发表时间：
2019-02-05
期刊：
Industrial health
影响因子：
2
作者：
Skornyakov E;Gaddameedhi S;Paech GM;Sparrow AR;Satterfield BC;Shattuck NL;Layton ME;Karatsoreos I;VAN Dongen HPA
通讯作者：
VAN Dongen HPA

UV-B-Induced Erythema in Human Skin: The Circadian Clock Is Ticking.