Defining the role of MC1R in UV-induced oxidative damage and DNA repair

定义 MC1R 在紫外线诱导的氧化损伤和 DNA 修复中的作用

• 批准号: 7321559
• 负责人: John A D'Orazio
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321559
• 关键词: Address; Adenylate Cyclase; Affect; Animal Model; Animals; Binding; Bypass; Chemicals; Chemoprotective Agent; Cyclic AMP; Cyclobutanes; DNA Damage; DNA Repair; Data; Defect; Event; Exposure to; Failure; Figs - dietary; Forskolin; Functional disorder; Generations; Genetic; Goals; Health; Hormones; Human; Incidence; Individual; Injury; Inorganic Sulfates; Lead; Link; Measures; Mediating; Melanins; Melanocortin 1 Receptor; Melanocyte stimulating hormone; Methods; Modeling; Molecular; Mus; Nucleotide Excision Repair; Phenotype; Pigmentation physiologic function; Pigments; Predisposition; Prevention strategy; Process; Production; Property; Proteins; Receptor Signaling; Reporting; Research; Risk Factors; Role; Signal Transduction; Skin; Skin Cancer; Testing; Tissues; Topical application; Transgenic Animals; UV Radiation Exposure; UV induced; UV sensitive; Ultraviolet Rays; Unspecified or Sulfate Ion Sulfates; Variant; alpha-Melanocyte stimulating hormone; base; carcinogenesis; congenic; defined contribution; design; dimer; eumelanin; insight; interest; melanocyte; melanoma; mouse model; novel; oxidative DNA damage; pheomelanin; receptor; receptor function; repaired; simulation; skin cancer prevention; small molecule; tool; ultraviolet damage

DESCRIPTION (provided by applicant): We are interested in deciphering the molecular basis of UV injury and carcinogenesis in the skin, with the long- term research objective of designing chemoprotective strategies against skin cancer. Fair skin correlates with enhanced expression of pheomelanin, a pigment with poor UV-blocking abilities, and reduced expression of eumelanin, a pigment with excellent UV-blocking properties. Logically, pheomelanotic individuals endure the highest incidence of UV-mediated damage, including skin cancer. Pigmentation is regulated by the binding of melanocortin stimulating hormone (MSH) to its cognate receptor, the melanocortin-1 receptor (MC1R), which in turn mediates adenylyl cyclase activation and subsequent production of cyclic AMP (cAMP). High functioning MC1R variants result in high levels of cAMP and eumelaninization, whereas low functioning MC1R variants lead to low levels of cAMP and pheomelanization. We have developed a novel mouse model that mimics human skin of different pigmentation (eumelanotic, pheomelanotic, and albino). We found that by topically applying a small molecule (forskolin) to the fair-skinned animals, eumelanin production was induced and the animals were UV-protected. Such forskolin-mediated eumelanin production likely occurs by directly activating adenylyl cyclase in melanocytes, thereby "by-passing" the defective MC1R signaling that causes fair skin in our model. We hypothesize that MC1R dysfunction leads to UV-dependent oxidative damage in the skin and defective repair of UV-mediated DNA damage. Further, we propose that topical forskolin protects against UV injury through eumelanin induction and rescue of DNA repair. Taking advantage of our unique murine model, we will determine the effect of pheomelanin on UV damage in the skin (Specific Aim aim 1), and define the contribution of MC1R function in the repair of UV-mediated damage (Specific Aim aim 2). In our studies, we will measure different types of UV-induced oxidative damage, analyze repair of this damage, and determine whether topical forskolin can modify these damage and repair profiles. Our findings will have significant health relatedness, as they will clarify longstanding questions regarding pheomelanin in oxidative damage and MC1R function in the repair of UV-induced damage. Most importantly, we anticipate that our resulting data will provide clear insight into effective, topical approaches to repairing UV-mediated skin damage and preventing skin cancer.

描述（由申请人提供）： 我们有兴趣破译皮肤紫外线损伤和致癌的分子基础，长期研究目标是设计针对皮肤癌的化学保护策略。白皙的皮肤与褐黑素（一种具有较差紫外线阻挡能力的色素）表达增强相关，而与真黑素（一种具有出色紫外线阻挡性能的色素）表达减少相关。从逻辑上讲，患有褐黑色素的人遭受紫外线介导的损伤（包括皮肤癌）的发生率最高。色素沉着是通过黑皮质素刺激激素 (MSH) 与其同源受体黑皮质素-1 受体 (MC1R) 的结合来调节的，而黑皮质素-1 受体 (MC1R) 反过来又介导腺苷酸环化酶的激活和随后的环 AMP (cAMP) 的产生。高功能的 MC1R 变异导致高水平的 cAMP 和真黑色素化，而低功能的 MC1R 变异导致低水平的 cAMP 和褐黑化。我们开发了一种新型小鼠模型，可以模仿不同色素沉着（真黑、褐黑和白化）的人类皮肤。我们发现，通过在皮肤白皙的动物身上局部涂抹小分子（毛喉素），可以诱导真黑色素的产生，并且动物受到紫外线保护。这种毛喉素介导的真黑素生成可能是通过直接激活黑素细胞中的腺苷酸环化酶来发生的，从而“绕过”了导致我们模型中皮肤白皙的有缺陷的 MC1R 信号传导。我们假设 MC1R 功能障碍会导致皮肤中紫外线依赖性氧化损伤以及紫外线介导的 DNA 损伤修复缺陷。此外，我们建议外用毛喉素通过诱导真黑色素和拯救 DNA 修复来防止紫外线损伤。利用我们独特的小鼠模型，我们将确定褐黑素对皮肤紫外线损伤的影响（具体目标 1），并确定 MC1R 功能在修复紫外线介导的损伤中的贡献（具体目标 2）。在我们的研究中，我们将测量不同类型的紫外线引起的氧化损伤，分析这种损伤的修复，并确定外用毛喉素是否可以改变这些损伤和修复情况。我们的研究结果将具有重要的健康相关性，因为它们将澄清有关氧化损伤中的褐黑素和修复紫外线引起的损伤中的 MC1R 功能的长期存在的问题。最重要的是，我们预计我们得到的数据将为修复紫外线介导的皮肤损伤和预防皮肤癌的有效局部方法提供清晰的见解。