Aging Stratum Corneum pH and Barrier Function

老化角质层pH值与屏障功能

• 批准号: 8309187
• 负责人: Theodora M Mauro
• 金额: $ 29.38万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309187
• 关键词: 6-carboxyfluorescein; Abbreviations; Acidity; Acids; Adult; Affect; Age; Aging; Animals; Area; Biopsy; Bypass; Cell membrane; Clinical; Complement; Defect; Disease; Down-Regulation; Dryness; Eczema; Enzymes; Epidermis; Family; Fluorescence; Future; Goals; Homeostasis; Human; Image; Immunoelectron Microscopy; Immunohistochemistry; Impairment; Individual; Inflammatory; Knockout Mice; Lead; Ligands; Lipids; Liver; Measures; Mediating; Methylguanidine; Microscopy; Mus; NHE1; Neonatal; Pattern; Permeability; Peroxisome Proliferator-Activated Receptors; Phospholipase; Phospholipase A2; Play; Predisposition; Process; Protein Isoforms; Proteins; Protocols documentation; Recovery; Relative (related person); Role; Severities; Skin; Skin Aging; Solutions; Stratum Granulosum; Stratum corneum; Techniques; Testing; Therapeutic; Thick; Water; Work; acronyms; aged; alveolar lamellar body; antiporter; compare effectiveness; glucosylceramidase; human subject; improved; inhibitor/antagonist; lactobionic acid; public health relevance; receptor; research study; resorufin; sPLA2 enzyme; skin disorder; small hairpin RNA; young adult

DESCRIPTION (provided by applicant): Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that can be traced to, or exacerbated by, impaired epidermal permeability barrier homeostasis. In contrast to extremely aged individuals, we find that moderately aged humans (50-80 years) and mice (12-15 mos) suffer from defective stratum corneum (SC) acidification. SC acidification is required to activate key pH-sensitive lipid processing enzymes, including beta-GlcCer'ase (beta-glucocerebrosidase). Neonatal and adult SC both are acidified largely through the combined activity of two endogenous mechanisms, the Na+/H+ antiporter (NHE1) and the secretory phospholipase (sPLA2) enzymes, although the relative contribution of each agent in supplying SC acidity to specific regions of the SC is not known. We previously found that NHE1 protein levels and full- thickness SC acidity are decreased in moderately aged mouse epidermis. We now propose to define the relative roles of NHE1 and sPLA2 in acidifying specific regions of the SC in young adult mouse and human epidermis, and determine what role abnormal NHE1 or sPLA2 expression, localization and/or function play in producing the abnormal acidification seen in aged SC. We will define the roles of the NHE1 and sPLA2 in both murine and human skin, and then delineate the responsible mechanisms in mouse skin and cultured human epidermal equivalents. Finally, we will explore a broad set of strategies aimed at normalizing SC acidification, either by upregulating sPLA2 activity, or by bypassing defective endogenous mechanisms with exogenous acidifying agents already approved for use in humans. HYPOTHESIS: Both the NHE1 transporter and one or more sPLA2 isoforms control SC barrier bulk acidification, or acidification of SC microdomains, where the pH-sensitive lipid processing enzymes that influence barrier homeostasis are selectively and locally activated. The NHE1 and sPLA2 complement each other in acidifying different layers and microdomains within normal young adult SC. Defects in one or both acidifying mechanisms result in suboptimal function in moderately aged epidermis, depending on the severity and localization of the age-associated pH abnormality. Enhancing SC acidity, either through increased sPLA2 activity, or by applying exogenous acidifying agents, will normalize lipid processing, thereby improving the clinical abnormalities in SC function seen in aged epidermis. The short-term goal of this project is to determine the pathophysiologic mechanisms by which SC acidity differs in aged vs. young SC. The long-term goal of this project is to restore epidermal permeability barrier homeostasis in aged skin, by optimizing the SC acidity that controls barrier homeostasis. PUBLIC HEALTH RELEVANCE: Information form these experiments will be used to optimize therapeutic protocols that restore effective epidermal barrier homeostasis in aged skin. As normal skin ages, it tends to become dry. This dryness makes even normal skin itchy, and makes skin that already is affected by common diseases, such as eczema, worse. Dry skin in moderately aged people (age 50-75 years) is caused by the loss of an epidermal barrier, made up of correctly processed lipids in the uppermost layer of the skin. Processing these lipids, in turn, depends on effectively acidifying this uppermost layer of the skin. We have found that even moderately aged skin is less acidic than skin of young adults, using a new non-invasive microscopy technique called fluorescence lifetime imaging. Further, we have found that applying acidic solutions to moderately aged skin restores skin acidity and normal lipid processing, thus improving the epidermal barrier. These experiments will study what mechanisms in the skin cause its uppermost layer to be acidified in young skin, what changes occur in aged skin that cause this acidification to be lost, and what therapies work best to restore acidity and a normal epidermal barrier to aged skin. These studies will show that it is possible to identify and treat a major cause of skin disease in the aged.

描述（由申请人提供）：老化的皮肤通常受到炎症性皮肤病或干燥/湿疹的折磨，这些疾病可追溯到或加重表皮渗透性屏障稳态受损。与极度衰老的个体相比，我们发现中度衰老的人类（50-80岁）和小鼠（12-15岁）患有角质层（SC）酸化缺陷。SC酸化需要激活关键的ph敏感脂质处理酶，包括β -葡萄糖脑苷酶（β -葡萄糖脑苷酶）。新生儿和成年SC的酸化主要是通过两种内源性机制的联合作用，即Na+/H+反转运蛋白（NHE1）和分泌磷脂酶（sPLA2）酶，尽管每种物质在向SC特定区域提供SC酸度方面的相对贡献尚不清楚。我们之前发现，在中等年龄的小鼠表皮中，NHE1蛋白水平和全层SC酸度下降。我们现在提议确定NHE1和sPLA2在年轻成年小鼠和人类表皮SC特定区域酸化中的相对作用，并确定NHE1或sPLA2异常表达、定位和/或功能在老年SC中产生异常酸化中的作用。我们将确定NHE1和sPLA2在小鼠和人类皮肤中的作用，然后描述小鼠皮肤和培养的人类表皮中的相关机制。最后，我们将探索一系列旨在使SC酸化正常化的策略，要么通过上调sPLA2活性，要么通过使用已批准用于人类的外源性酸化剂绕过有缺陷的内源性机制。假设：NHE1转运体和一个或多个sPLA2亚型控制SC屏障的整体酸化，或SC微结构域的酸化，其中影响屏障稳态的ph敏感脂质处理酶被选择性和局部激活。在正常青年SC中，NHE1和sPLA2在酸化不同层和微结构域方面是互补的。一种或两种酸化机制的缺陷会导致中度衰老表皮的次优功能，这取决于与年龄相关的pH异常的严重程度和定位。通过增加sPLA2活性或使用外源性酸化剂来增强SC的酸度，将使脂质加工正常化，从而改善衰老表皮中SC功能的临床异常。这个项目的短期目标是确定衰老和年轻皮肤中SC酸度差异的病理生理机制。这个项目的长期目标是通过优化控制屏障稳态的SC酸度来恢复衰老皮肤的表皮渗透性屏障稳态。

项目成果

Basis for enhanced barrier function of pigmented skin.

• DOI: 10.1038/jid.2014.187
• 发表时间: 2014-09
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Man, Mao-Qiang;Lin, Tzu-Kai;Santiago, Juan L.;Celli, Anna;Zhong, Lily;Huang, Zhi-Ming;Roelandt, Truus;Hupe, Melanie;Sundberg, John P.;Silva, Kathleen A.;Crumrine, Debra;Martin-Ezquerra, Gemma;Trullas, Caries;Sun, Richard;Wakefield, Joan S.;Wei, Maria L.;Feingold, Kenneth R.;Mauro, Theodora M.;Elias, Peter M.
• 通讯作者: Elias, Peter M.

Acidification in the epidermis and the role of secretory phospholipases.

• DOI: 10.4161/derm.3.2.15140
• 发表时间: 2011-04
• 期刊: Dermato-endocrinology
• 作者: Chan A;Mauro T
• 通讯作者: Mauro T