Melanocyte-Keratinocyte Cross-Talk In Relation To Barrier Function

黑素细胞-角质形成细胞与屏障功能的交互作用

基本信息

批准号：
8271286
负责人：
Peter M Elias
金额：
$ 32.01万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271286
关键词：
Accounting Acetone Actins Acute Adult Affect Agonist Air Area Atopic Dermatitis Biological Models Cell Culture Techniques Cells Characteristics Coculture Techniques Confocal Microscopy Cutaneous Defect Development Disease susceptibility Distal Dose Eczema Enzymes Epidermis Ethnic Origin Exhibits Exocytosis Exposure to Eye FGF2 gene Glycine decarboxylase Gold Growth Hair follicle structure Health Health Status Homeostasis Homologous Gene Human Humidity In Vitro Individual Infection Infectious Skin Diseases Inflammatory Interleukin-1 Keratin Latex Link Measures Melanins Melanocyte stimulating hormone Melanogenesis Melanosomes Metabolic Methods Microphthalmos Mixed Function Oxygenases Modeling Monophenol Monooxygenase Motor Mus Mutant Strains Mice Mutation Myosin ATPase Oculocutaneous albinism type 1 Oculocutaneous albinism type 2 Permeability Physiological Pigmentation physiologic function Pigments Preparation Primates Process Production Proteins Proteolytic Processing Psoriasis Publishing Race Relative (related person)Research Risk Rodent Role Signal Transduction Site Skin Solvents Stem Cell Factor Stimulus Stratum Basale Stratum corneum Stress Surface Swab Syndrome Transgenic Mice Veterans albino mouse antimicrobial antimicrobial peptide base chromogranin A (344-364)cohesion density disorder prevention feeding improved in vivo insight keratinocyte melanocyte migration mouse model mutant mouse model paracrine promoter prototype receptor repaired response restoration sensor skin disorder stressor synthetic enzyme transcription factor vapor

项目摘要

DESCRIPTION (provided by applicant): We have shown that dark pigmentation independent of race or ethnicity, endows the epidermis with enhanced barrier function and antimicrobial defense. As a result, lightly-pigmented skin should be inherently more at risk for development of inflammatory skin disorders, such as atopic dermatitis and adult eczemas, well as all types of skin infections. But the basis for the link between pigmentation and epidermal function remains unknown. Using organotypic human keratinocyte cultures, grown with melanocytes, as well as selected mouse models, we will assess first, the role of melanocyte density and the extent of melanocyte pigmentation in regulating epidermal function. The functional end-points will comprise changes in permeability barrier homeostasis, stratum corneum (SC) integrity/cohesion, and expression of certain key antimicrobial peptides that contribute to cutaneous antimicrobial defense. Since our recent studies suggest that darkly-pigmented melanocytes influence epidermal function by acidifying the outer epidermis, we next will assess the cellular basis for epidermal acidification by melanocytes; and then in mutant mouse models, which step in melanosome formation, acidification, or secretion regulates this process. If acidification alone fails to account for the impact of melanocytes on epidermal function, we plan to search for other melanocyte-initiated regulatory signals that influence epidermal function in a paracrine fashion. In Aim 3 we will examine the converse issue; i.e., how alterations in epidermal barrier requirements, elevations in surface pH, or a reduced environmental humidity ( UV-B) could regulate interfollicular (epidermal ) pigmentation, which then would improve barrier function in a feed forward fashion. Our prior studies have already shown that barrier disruption increases both IL-1a and NGF production, and that dose of UV-B that damage the barrier upregulate p53 expression. These signals are known to either increase epidermal pigmentation by increasing epidermal POMC expression and proteolytic processing to aMSH, and/or MC1R signalling of melanocyte function. We have identified two other keratinocyte regulatory signals could also link changes in epidermal barrier function to pigmentation; i.e., i) epidermal stem cell factor, which induces melanocytes to migrate from follicles to interfollicular epidermis; and ii) the transcription factor, foxn1, which targets melanocytes to the basal layer. We will assess whether altered barrier requirements regulate one or more of these 5 signaling mechanisms, leading to increased expression or activity of the key downstream enzymes of melanin production; i.e., tyrosinase, tyrosinase hydroxylase, and/or melanosome acidification. Finally, we will assess whether TRPV4, the epidermal sensor or external humidity, regulates pigmentary responses to decreased environmental humidity. Together, these studies will provide new insights into the role of pigmentation in regulating epidermal function, potentially explaining differences in disease susceptibility in different pigment groups, and perhaps leading to disease prevention in lightly-pigmented epidermis. Conversely, they should pinpoint epidermal-derived signals that regulate the development of interfollicular pigmentation in response to exogenous stress. PUBLIC HEALTH RELEVANCE: Decreased pigmentation reduces veterans' threshold for the development of inflammatory skin conditions and infections; while conversely, more pigmentation provides protection. These studies will reveal mechanisms whereby melanocytes regulate epidermal function, and vice-versa; i.e., how epidermal functional requirements in turn regulate pigmentation. Our research could point to straight-forward methods that could improve the health status of individuals at risk due to fair pigmentation, including veterans with atopic dermatitis and psoriasis.

描述（由申请人提供）：我们已经表明，深色色素沉着独立于种族或种族，使表皮具有增强的屏障功能和抗菌防御。结果，淡色调的皮肤本质上应该更有可能发育炎症性皮肤疾病的风险，例如特应性皮炎和成人湿疹，以及所有类型的皮肤感染。但是，色素沉着与表皮功能之间的联系的基础仍然未知。我们将使用具有黑素细胞生长的器官角质形成细胞培养物以及选定的小鼠模型，我们将首先评估黑素细胞密度的作用以及黑素细胞色素沉着在调节表皮功能中的作用。功能性终点将包括渗透性屏障稳态，角质层（SC）完整性/内聚力以及某些有助于皮肤抗微生物防御的某些关键抗菌肽的表达。自从我们最近的研究表明，黑色的黑素细胞通过酸化外表皮会影响表皮功能，接下来我们将评估黑素细胞表皮酸化的细胞基础。然后，在突变小鼠模型中，在黑素体形成，酸化或分泌的过程中，调节了这一过程。如果仅酸化就无法解释黑素细胞对表皮功能的影响，我们计划搜索其他黑色素细胞引发的调节信号，这些信号以旁分泌方式影响表皮功能。在AIM 3中，我们将研究相反的问题；也就是说，表皮屏障需求的改变，表面pH值的高程或环境湿度降低（UV-B）如何调节流体界面（表皮）色素沉着，然后以饲料向前的方式改善屏障功能。我们先前的研究已经表明，屏障破坏会增加IL-1A和NGF的产生，并且损害屏障上调p53表达的UV-B剂量。已知这些信号通过将表皮POMC表达和蛋白水解处理增加到AMSH和/或MC1R信号传导来增加表皮色素沉着。我们已经确定了其他两个角质形成细胞调节信号也可以将表皮屏障功能的变化与色素沉着联系起来。即，i）表皮干细胞因子，该因子诱导黑素细胞从卵泡迁移到毛囊表皮； ii）转录因子FOXN1，将黑素细胞靶向基础层。我们将评估改变的屏障需求是否调节了这5种信号传导机制中的一个或多个，从而导致黑色素产生的关键下游酶的表达或活性增加；即，酪氨酸酶，酪氨酸酶羟化酶和/或黑色素体酸化。最后，我们将评估TRPV4，表皮传感器或外部湿度是调节对环境湿度降低的色素反应。总之，这些研究将提供有关色素沉着在调节表皮功能中的作用的新见解，可能解释了不同色素组的疾病敏感性差异，并可能导致预防较轻的表皮疾病。相反，他们应确定表皮衍生的信号，以响应外源性应激，调节了流体色素沉着的发展。公共卫生相关性：色素沉着的降低会降低退伍军人在炎症性皮肤状况和感染的发展中的阈值；虽然相反，更多的色素沉着提供了保护。这些研究将揭示黑素细胞调节表皮功能的机制，反之亦然。即表皮功能需求又如何调节色素沉着。我们的研究可能指出了直截了当的方法，可以改善因色素沉着而带来的风险的个人的健康状况，包括患有特应性皮炎和牛皮癣的退伍军人。