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：
8675728
负责人：
ANDRZEJ T SLOMINSKI
金额：
$ 14.29万
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 2015-04-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675728
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）：假定在脊椎动物中，褪黑激素仅在松果体和视网膜中产生。然而，有证据表明，在脊椎动物，无脊椎动物，植物，单细胞真核生物，藻类，藻类甚至细菌中发现褪黑激素在整个自然界都可以广泛检测到。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室。褪黑激素（两栖甲氧吲哚）具有多效生物活性，如神经递质，激素，细胞因子和生物反应修饰剂，它们是通过与高亲和力受体相互作用介导的。褪黑激素也是一种广谱抗氧化剂，并通过受体独立的方式起作用，它激活了细胞保护途径，并在高浓度下会减弱或抵消氧化应激。这些抗氧化作用也通过其代谢产物N1-乙酰基-N2-甲酰基-5-甲氧基金素胺（AFMK）共享，这是褪黑激素代谢的最古老的产物。因此，褪黑激素表现出许多对不良应力响应系统极为有用的特性。因此，我们提出，皮肤褪黑激素能系统通过内部，自身或旁分泌机制来使细胞特异性的选择性，这些机制允许局部抵抗环境压力和内源性压力源保持皮肤完整性，而与昼夜节律的皮肤完整性保持无关，而与昼夜节律的皮肤融合蛋白融合蛋白分泌无关。这样的功能应包括激活细胞保护途径和抗凋亡途径，以及抗寄生虫，抗原毒性和抗癌激活岩。褪黑激素的生物活性将取决于先前存在的局部降解途径以及暴露于紫外线辐射（UVR）的强度，例如，通过活性氧或UVB的作用，可以将褪黑激素转化为AFMK，从而非酶上将其转化为AFMK。因此，我们提出的是：1。使用表皮角质形成细胞和甲状腺细胞在体外和人类皮肤外植体培养的杂种细胞和人类皮肤外植物组织培养的病态培养； 2。定义褪黑激素在调节黑素发生中的作用； 3。为培养的人角质形成细胞和黑素细胞中褪黑激素降解的途径。这些目的的实现将定义褪黑激素是否可以作为具有抗遗传毒性特性的一般“皮肤存活因子”，还是基因组和细胞完整性的“监护人”。因此，它可以用作防晒霜的组成部分或色素疾病的治疗（例如白癜风或色素沉着），增殖过程（包括癌性状态，表皮癌甚至黑色素瘤），UVB诱发的病理学，炎症性皮肤病和皮肤衰老。