Elucidating melatonin-regulated mechanisms of melanogenesis in human full-thickness skin and human melanocytes exposed to ultraviolet radiation

阐明暴露于紫外线辐射的人体全层皮肤和人体黑素细胞中褪黑激素调节黑素生成的机制

• 批准号: 350562430
• 负责人: Privatdozent Dr. Konrad Kleszczynski, Ph.D.
• 金额: --
• 依托单位: Klinik für Hautkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/350562430?language=en
• 关键词: Elucidating; melatonin; regulated; mechanisms; melanogenesis

Clinical disorders related to skin pigmentation include hypo- or hyperpigmentation, therefore active and safe pigment modulatory agents are strongly desired. Based on the so far described high biological activity of melatonin, it can be a potent substance that effectively controls mechanisms of melanogenesis. Melatonin (N-acetyl-5-methoxytryptamine) is a secretory product of the vertebrate pineal gland modulating various functions including scavenging free radicals, DNA repair or anti-apoptotic activity. It is also implicated in skin functions such as epidermal proliferation/differentiation, hair growth and melanoma/squamous cell carcinoma control. In this research application, it is proposed to evaluate the potential impact of melatonin on regulatory mechanisms of melanogenesis. So far wide-range experience gained by the applicant in the field of melatonin allows him to conduct all experiments enclosed in this proposal. The planed investigations will be carried out in human ex vivo full-thickness skin (PART I) with additional PART II using normal human melanocytes (NHM) in pure culture in comparison to co-culture with normal human keratinocytes (NHEK) that will reflect skin physiology in vivo. Additionally, such approach may describe the keratinocyte-melanocyte interaction as well as the key role of keratinocyte-dependent regulation of melanogenesis. In skin, the role and action of melatonin will be evaluated with respect to UVR-mediated melanogenesis including melatonins impact on tyrosinase (TYR), one of the key enzymes in melanogenesis, controlling the expression of microphtalmia-associated transcription factor (MITF) as well as the effect of melatonin on melanin synthesis and cAMP-PKA-MITF axis. Furthermore, a set of analysis will be performed with the earlier mentioned cell lines, i.e. NHM, NHEK, and this part together with data obtained from the first one is supposed to provide a comprehensive knowledge over the molecular way of action of melatonin-regulated melanogenesis. In both, experimental models, silencing of melanogenesis-dependent genes will be performed in order to investigate whether melatonin may maintain this process in case of alterations within these genes. Resulting findings undoubtedly will put in a brand new insight into the role of melatonin in cutaneous melanogenesis under UVR conditions and provide new principles for treatment of pigmentary disorders.

与皮肤色素沉着相关的临床病症包括色素沉着不足或色素沉着过度，因此强烈需要活性且安全的色素调节剂。基于迄今为止描述的褪黑激素的高生物活性，它可以是有效控制黑素生成机制的有效物质。褪黑激素（Melatonin，N-乙酰基-5-甲氧基色胺）是脊椎动物松果体的分泌产物，具有清除自由基、DNA修复和抗凋亡等多种功能。它还涉及皮肤功能，如表皮增殖/分化、毛发生长和黑色素瘤/鳞状细胞癌控制。在这项研究应用中，建议评估褪黑激素对黑素生成的调节机制的潜在影响。到目前为止，申请人在褪黑激素领域获得的广泛经验允许他进行本提案中所包含的所有实验。计划的研究将在人离体全层皮肤（第I部分）中进行，额外的第II部分使用纯培养的正常人黑素细胞（NHM）与正常人角质形成细胞（NHEK）共培养进行比较，这将反映体内皮肤生理学。此外，这种方法可以描述角质形成细胞-黑素细胞的相互作用，以及角质形成细胞依赖性调节黑素生成的关键作用。在皮肤中，褪黑激素的作用和行动将被评估的紫外线介导的黑色素生成，包括褪黑激素对酪氨酸酶（TYR）的影响，黑色素生成的关键酶之一，控制小眼症相关转录因子（MITF）的表达，以及褪黑激素对黑色素合成和cAMP-PKA-MITF轴的影响。此外，将用前面提到的细胞系，即NHM、NHEK进行一组分析，并且这一部分与从第一部分获得的数据一起被认为提供关于褪黑激素调节的黑素生成的分子作用方式的全面知识。在这两种实验模型中，将进行黑素生成依赖性基因的沉默，以研究在这些基因内发生改变的情况下褪黑激素是否可以维持该过程。这一发现无疑将为紫外线辐射条件下褪黑素在皮肤黑素生成中的作用提供一个全新的视角，并为色素性疾病的治疗提供新的原则。