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Signaling Pathways for UV-Induced Melanogenic Response

紫外线诱导的黑色素生成反应的信号通路

基本信息

批准号：
7902757
负责人：
ZALFA ABDEL-MALEK
金额：
$ 9.85万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2010-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7902757
关键词：
Accounting Adenylate Cyclase Affect Agonist Alleles Apoptosis Applications Grants Arrestins Binding Biological Assay Cell Surface Receptors Cell membrane Cell surface Cells Chronic Clathrin-Coated Vesicles Congenital Megacolon Corticotropin Country Coupling Cutaneous Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP-Dependent Protein Kinases DNA Damage Data Dominant-Negative Mutation Early Endosome Electron Microscopy Endothelin B Receptor Endothelin Receptor Endothelin-1 Epidermis Funding GTP-Binding Proteins Gene Expression Generations Genes Genetic Polymorphism Genetic Transcription Genetic Variation Genome Stability Genotype Goals Grant Human Hydrogen Peroxide Immunoprecipitation Incidence Individual Kinetics Knowledge Label Lead Ligands Lysosomes Malignant - descriptor Measures Melanocortin 1 Receptor Melanocyte stimulating hormone Melanoma Cell Membrane Membrane Protein Traffic Messenger RNA Molecular Monitor Mutation National Institute of Environmental Health Sciences Non-Malignant Nucleotide Excision Repair Outcome Oxidative Stress Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiologic pulse Physiological Pigmentation physiologic function Pigments Play Predisposition Prevention strategy Protein Dephosphorylation Proteins Proteolysis Public Health Radiation Radiation Induced DNA Damage Receptor Activation Receptor Gene Recycling Regulation Reporting Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Signal Pathway Skin Cancer Skin Carcinoma Skin tanning Study Section Surface Susceptibility Gene Testing Time Transcriptional Regulation Transmembrane Domain UVB induced Ultraviolet Rays Western Blotting advanced disease agouti protein alpha-Melanocyte stimulating hormone arrestin 1 arrestin 2 base brief intervention cell type desensitization effective therapy eumelanin exposed human population high risk loss of function melanocortin receptor melanocyte melanoma novel paracrine photoprotection prevent protein activation protein expression public health relevance receptor receptor binding receptor coupling receptor expression receptor internalization receptor recycling research study response trafficking

项目摘要

DESCRIPTION (provided by applicant): This competing renewal application aims at investigating the hypothesis that exposure of human melanocytes to ultraviolet radiation (UV) and/or the physiological agonist 1-melanocyte stimulating hormone (1-MSH) or antagonist agouti signaling protein (ASIP) modulates the expression of the melanocortin 1 receptor (MC1R) gene, and regulates the activation of the receptor by affecting its desensitization, internalization and resensitization. The MC1R is a Gs protein-coupled receptor with seven transmembrane domains that is expressed on human melanocytes. Activation of this receptor by its agonists 1-MSH or ACTH stimulates cAMP formation and the synthesis of the brown-black eumelanin, which confers cutaneous photoprotection. We have shown that activation of the MC1R is pivotal for the UV-induced tanning response, and importantly, reduces the extent of UV-induced DNA damage by enhancing nucleotide excision repair and counteracting oxidative stress in human melanocytes. These effects explain why loss-of-function alleles of the MC1R are associated with increased risk for melanoma. We are proposing that MC1R expression and function are regulated at different levels in response to UV, its physiological agonists and antagonist. To investigate the above stated hypothesis, we propose the following three Specific Aims. First, we will investigate the regulation of MC1R gene expression and receptor trafficking by real time RT-PCR, Western blotting, and immunostaining. Second, we will determine the activation of the MC1R, by quantitating the number of membrane receptors/melanocyte, its agonist-induced desensitization, internalization, and resensitization. Third, we will define the roles of G protein receptor kinases (GRKs) and 2-arrestins in MC1R surface expression and sequestration. The significance of the proposed studies lies in the critical role of the MC1R and melanocortins in the UV responses of human melanocytes, and in filling the gap in the existing knowledge about regulation of this receptor in the physiologically-relevant cell, the epidermal melanocyte. Given that the MC1R is a melanoma susceptibility gene and an important determinant of the UV-induced tanning response, elucidating the regulation of MC1R expression and activation will lead to new strategies to prevent melanoma and other types of skin cancer by increasing the activity of the MC1R and optimizing the photoprotective capacity of the melanocyte, particularly in high risk individuals. PUBLIC HEALTH RELEVANCE The outcome of this grant application is expected to lead to new strategies for prevention of melanoma, the deadliest form of skin cancer, and of non-melanoma skin cancers. These strategies will be based on modulating the activity of the melanocortin 1 receptor by mechanisms that will be elucidated during the course of this grant proposal. The incidence of melanoma in the U.S. and Eastern countries continues to rise with no effective treatment for advanced disease; hence the relevance of this project for public health.

描述（申请人提供）：该竞争性更新申请旨在研究以下假设：人黑素细胞暴露于紫外线辐射（UV）和/或生理激动剂1-黑素细胞刺激激素（1-MSH）或拮抗剂促黑素细胞激素信号传导蛋白（ASIP）调节黑皮质素1受体（MC 1 R）基因的表达，并通过影响其脱敏来调节受体的激活，内化和再敏感化。MC 1 R是一种具有7个跨膜结构域的Gs蛋白偶联受体，在人黑素细胞上表达。通过其激动剂1-MSH或ACTH激活该受体，刺激cAMP形成和棕黑色真黑素的合成，其赋予皮肤光保护。我们已经表明，MC 1 R的激活是紫外线诱导的晒黑反应的关键，并且重要的是，通过增强核苷酸切除修复和抵消人黑素细胞中的氧化应激来降低紫外线诱导的DNA损伤的程度。这些效应解释了为什么MC 1 R的功能丧失等位基因与黑色素瘤风险增加相关。我们提出，MC 1 R的表达和功能调节在不同的水平上响应UV，其生理激动剂和拮抗剂。为了研究上述假设，我们提出了以下三个具体目标。首先，我们将通过真实的时间RT-PCR、蛋白质印迹和免疫染色来研究MC 1 R基因表达和受体运输的调控。其次，我们将通过定量膜受体/黑素细胞的数量、其激动剂诱导的脱敏、内化和再敏化来确定MC 1 R的激活。第三，我们将确定G蛋白受体激酶（GRKs）和2-arrestins在MC 1 R表面表达和隔离的作用。所提出的研究的意义在于MC 1 R和黑皮质素在人黑素细胞的UV响应中的关键作用，以及填补了关于生理相关细胞（表皮黑素细胞）中该受体的调节的现有知识中的差距。鉴于MC 1 R是黑色素瘤易感基因和UV诱导的晒黑反应的重要决定因素，阐明MC 1 R表达和活化的调节将导致通过增加MC 1 R的活性和优化黑色素细胞的光保护能力来预防黑色素瘤和其他类型的皮肤癌的新策略，特别是在高风险个体中。这项拨款申请的结果预计将导致预防黑色素瘤（最致命的皮肤癌形式）和非黑色素瘤皮肤癌的新策略。这些策略将基于调节黑皮质素1受体的活性，其机制将在本拨款申请过程中阐明。黑色素瘤在美国和东方国家的发病率持续上升，没有有效的治疗晚期疾病;因此，该项目与公共卫生的相关性。