Role of exogenous melatonin in skin biology

外源性褪黑激素在皮肤生物学中的作用

基本信息

批准号：
8476985
负责人：
ANDRZEJ T SLOMINSKI
金额：
$ 31.64万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476985
关键词：
Affinity Aging Agonist Algae Antioxidants Apoptotic Attenuated Bacteria Behavior Binding Biochemical Biological Biological Response Modifiers Biology Buffers Cells Chemicals Circadian Rhythms Cosmetics Cutaneous Degradation Pathway Disease Dissection Dose Epidermis Eukaryota Exhibits Gene Silencing Genome Homeostasis Hormones Human Hyperpigmentation In Vitro Inflammatory Invertebrates Malignant Neoplasms Measures Mediating Melanogenesis Melatonin Membrane Metabolism Mitochondria Molecular Nature Neurotransmitters Nuclear Nuclear Receptors Oxidative Stress Pathology Pathway interactions Phenotype Pigmentation physiologic function Pineal gland Plants Precancerous Conditions Process Production Property Proteins Quinone Reductases Radiation induced damage Reactive Oxygen Species Receptor, Melatonin, MT2 Regulation Retina Role Serotonin Skin Skin Aging Specificity Stress Structure Sunscreening Agents System Technology Testing Therapeutic Tryptophan UV Radiation Exposure Ultraviolet B Radiation Vertebrates Vitiligo autocrine biological adaptation to stress clinical application cytokine keratinocyte melanocyte melanoma methoxyindole novel therapeutics paracrine receptor skin disorder stressor

项目摘要

DESCRIPTION (provided by applicant): It was assumed that in vertebrates melatonin is only produced in the pineal gland and retina. However, evidence has accumulated that melatonin is widely detectable throughout Nature, being found in vertebrates, invertebrates, plants, unicellular eukaryotes, algae and even bacteria. We have documented that melatonin is produced and metabolized by the mammalian skin, where it can permeate to all cellular compartments including mitochondria. Melatonin (an amphilic methoxyindole) has pleiotropic bioactivities, as neurotransmitter, hormone, cytokine and biological response modifier, which are mediated by interactions with high affinity receptors. Melatonin is also a broad-spectrum antioxidant and acting via receptor-independent manner it activates cytoprotective pathways and at high concentrations it attenuates or counteracts the oxidative stress. These antioxidant effects are also shared by its metabolite, N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK), phylogenetically the oldest product of melatonin metabolism. Thus, melatonin exhibits a number of properties that are extremely useful for the integumental stress-response systems. Accordingly, we have proposed that the cutaneous melatoninergic system enables for cell-specific selectivity through intra-, auto- or paracrine mechanisms, which allow locally counteracting or buffering both environmental and endogenous stressors to maintain skin integrity, independent of circadian pineal melatonin secretion. Such functions should include activation of cytoprotective and anti-apoptotic pathways, and antimutagenic, antigenotoxic and anticancerogenic activites. Melatonin bioactivity would depend on preexistent local degradative pathways and the intensity of exposure to ultraviolet radiation (UVR), e.g., melatonin can be converted non-enzymatically to AFMK through action of reactive oxygen species or UVB. Therefore, we are proposing: 1. To define the protective role of melatonin in human epidermis using epidermal keratinocytes and melanocytes cultured in vitro and human skin explants histocultured ex-vivo; 2. To define the role of melatonin in regulation of melanogenesis; 3. To characterize the pathway of melatonin degradation in cultured human keratinocytes and melanocytes. Realization of these aims will define whether melatonin can be exploited therapeutically, either as a general "skin survival factor" with anti- genotoxic properties or as a "guardian" of genome and cellular integrity. Thus, it may be used as a component of sunscreens or in the treatment of pigmentary diseases (e.g. vitiligo or hyperpigmentation), proliferative processes (including precancerous states, epidermal cancer or even melanoma), UVB-induced pathology, inflammatory dermatoses and skin aging.

描述（由申请人提供）：假设脊椎动物中褪黑激素仅在松果体和视网膜中产生。然而，越来越多的证据表明，褪黑激素在自然界中广泛存在，在脊椎动物、无脊椎动物、植物、单细胞真核生物、藻类甚至细菌中都有发现。我们已经证明，褪黑激素是由哺乳动物皮肤产生和代谢的，它可以渗透到包括线粒体在内的所有细胞区室。褪黑素（一种两亲性甲氧基吲哚）具有多效性生物活性，如神经递质、激素、细胞因子和生物反应调节剂，这些生物活性通过与高亲和力受体的相互作用介导。褪黑激素也是一种广谱抗氧化剂，通过不依赖于受体的方式发挥作用，激活细胞保护途径，在高浓度时，它可以减弱或抵消氧化应激。其代谢物 N1-乙酰基-N2-甲酰基-5-甲氧基犬尿胺 (AFMK) 也具有这些抗氧化作用，AFMK 在系统发育上是褪黑素代谢最古老的产物。因此，褪黑激素表现出许多对外皮应激反应系统极其有用的特性。因此，我们提出，皮肤褪黑激素系统能够通过内分泌、自分泌或旁分泌机制实现细胞特异性选择性，从而局部抵消或缓冲环境和内源性应激源，以维持皮肤完整性，而不受昼夜节律松果体褪黑激素分泌的影响。这些功能应包括细胞保护和抗凋亡途径的激活，以及抗突变、抗原毒性和抗癌活性。褪黑激素的生物活性取决于预先存在的局部降解途径和暴露于紫外线辐射 (UVR) 的强度，例如，褪黑激素可以通过活性氧或 UVB 的作用以非酶促方式转化为 AFMK。因此，我们建议： 1. 利用体外培养的表皮角质形成细胞和黑素细胞以及离体组织培养的人皮肤外植体，明确褪黑素对人表皮的保护作用； 2. 明确褪黑激素在黑色素生成调节中的作用； 3. 表征培养的人角质形成细胞和黑素细胞中褪黑激素的降解途径。这些目标的实现将决定褪黑激素是否可以用于治疗，或者作为具有抗基因毒性的一般“皮肤存活因子”，或者作为基因组和细胞完整性的“守护者”。因此，它可以用作防晒霜的成分或用于治疗色素性疾病（例如白癜风或色素沉着过度）、增殖过程（包括癌前状态、表皮癌甚至黑色素瘤）、UVB诱导的病理、炎症性皮肤病和皮肤老化。