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（由申请人提供）：这种竞争性更新申请旨在调查人类黑色素细胞暴露于紫外线辐射（UV）和/或生理激动剂1-甲状腺素刺激激素（1-MSH）或拮抗剂AGOUTI信号蛋白（ASIP）的表达1-甲虫的表达1-甲基素体（1-MSH）的表达，以下假设。通过影响其脱敏，内在化和敏化来激活受体。 MC1R是一种GS蛋白偶联受体，具有七个在人黑色素细胞上表达的跨膜结构域。该受体的激动剂1-MSH或ACTH激活该受体刺激cAMP的形成和棕色黑色eumelanin的合成，这使皮肤光保护赋予。我们已经表明，MC1R的激活对于紫外线诱导的晒黑反应是关键的，重要的是，通过增强核苷酸切除修复并抵消人类黑素细胞中氧化应激，从而降低了UV诱导的DNA损伤的程度。这些影响解释了为什么MC1R的功能丧失等位基因与黑色素瘤风险增加有关。我们提出，MC1R表达和功能是根据紫外线（其生理激动剂和拮抗剂）在不同水平下的调节。为了研究上述假设，我们提出以下三个特定目标。首先，我们将根据实时RT-PCR，Western blotting和Ammunosing研究MC1R基因表达和受体运输的调节。其次，我们将通过量化膜受体/黑素细胞的数量，其激动剂诱导的脱敏，内在化和脱敏化来确定MC1R的激活。第三，我们将定义G蛋白受体激酶（GRKS）和2-次素在MC1R表面表达和隔离中的作用。拟议研究的重要性在于MC1R和黑色素皮质素在人类黑色素细胞的UV反应中的关键作用，以及在现有的有关该受体在生理上相关的细胞中调节该受体的知识的空白，表皮黑素细胞。鉴于MC1R是黑色素瘤敏感性基因，并且是紫外线诱导的晒黑反应的重要决定因素，阐明了MC1R表达和激活的调节，将导致新的策略，以通过增加MC1R的活性，并优化高风险个体的光学保护能力，从而预防黑色素瘤和其他类型的皮肤癌。公共卫生相关性预计该赠款申请的结果将导致预防黑色素瘤，最致命的皮肤癌和非黑色素瘤皮肤癌的新策略。这些策略将基于通过在本赠款建议过程中阐明的机制来调节黑素皮质1受体的活性。美国和东部国家的黑色素瘤发病率继续增加，没有有效治疗晚期疾病。因此，该项目与公共卫生的相关性。