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

• 批准号: 8110569
• 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
• 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/8110569
• 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 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; public health relevance; receptor; repaired; response; restoration; sensor; skin disorder; stressor; synthetic enzyme; transcription factor; vapor

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）：我们已经证明，与种族或民族无关的深色色素沉着赋予表皮增强的屏障功能和抗菌防御能力。因此，浅色皮肤本质上更容易患炎症性皮肤病，例如特应性皮炎和成人湿疹，以及所有类型的皮肤感染。但色素沉着和表皮功能之间联系的基础仍然未知。使用与黑素细胞一起生长的器官型人类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和黑素细胞色素沉着的程度在调节表皮功能中的作用。功能终点将包括渗透屏障稳态、角质层 (SC) 完整性/内聚力以及有助于皮肤抗菌防御的某些关键抗菌肽表达的变化。 由于我们最近的研究表明深色黑色素细胞通过酸化外表皮来影响表皮功能，因此我们接下来将评估黑色素细胞表皮酸化的细胞基础；然后在突变小鼠模型中，黑素体形成、酸化或分泌的步骤调节这一过程。如果单独的酸化不能解释黑素细胞对表皮功能的影响，我们计划寻找其他黑素细胞发起的以旁分泌方式影响表皮功能的调节信号。 在目标 3 中，我们将研究相反的问题；即，表皮屏障要求的改变、表面 pH 值的升高或环境湿度 (UV-B) 的降低如何调节毛囊间（表皮）色素沉着，从而以前馈方式改善屏障功能。我们之前的研究已经表明，屏障破坏会增加 IL-1a 和 NGF 的产生，而破坏屏障的 UV-B 剂量会上调 p53 表达。已知这些信号通过增加表皮 POMC 表达和 aMSH 的蛋白水解加工来增加表皮色素沉着，和/或黑素细胞功能的 MC1R 信号传导。我们已经发现另外两种角质形成细胞调节信号也可能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，其诱导黑素细胞从毛囊迁移至毛囊间表皮； ii) 转录因子foxn1，将黑素细胞靶向基底层。我们将评估屏障要求的改变是否调节这 5 种信号机制中的一种或多种，​​从而导致黑色素生成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/或黑素体酸化。最后，我们将评估 TRPV4（表皮传感器或外部湿度）是否调节色素对环境湿度降低的反应。总之，这些研究将为色素沉着在调节表皮功能中的作用提供新的见解，可能解释不同色素组疾病易感性的差异，并可能导致浅色素表皮的疾病预防。相反，他们应该查明表皮衍生的信号，这些信号调节毛囊间色素沉着的发展以响应外源压力。 公共健康相关性：色素沉着减少可降低退伍军人发生炎症性皮肤病和感染的阈值；相反，更多的色素沉着可以提供保护。这些研究将揭示黑素细胞调节表皮功能的机制，反之亦然；即表皮功能需求如何反过来调节色素沉着。我们的研究可以指出直接的方法，可以改善因色素沉着而面临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。