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Stratum Corneum Acidification in the Neonate

新生儿角质层酸化

基本信息

批准号：
7253374
负责人：
KENNETH R FEINGOLD
金额：
$ 32.32万
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：
1994
资助国家：
美国
起止时间：
1994-05-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7253374
关键词：
Acceleration Accounting Acids Acute Adult Age Animal Experiments Animals Biochemical Biological Assay Birth Clofibrate Cutaneous Cytosol Defect Development Disruption Eccrine Glands Endopeptidases Enzymes Epidermis Exhibits Extracellular Space Fetal Development Funding Generations Grant Histidine Histidine Ammonia-Lyase Homeostasis Human Hydrolysis Individual Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Knockout Mice Laboratories Lead Ligands Lipids Localized Mammals Measures Mediating Membrane Messenger RNA Modeling Molecular Mus NHE1 Nature Neonatal Newborn Animals Newborn Infant Nonesterified Fatty Acids Nuclear Hormone Receptors PPAR alpha PPAR delta Pathway interactions Peptide Hydrolases Permeability Peroxisome Proliferator-Activated Receptors Phospholipase A2 Phospholipid Metabolism Phospholipids Predisposition Process Proteins Proteolysis Protons Rate Rattus Recovery Regulation Rodent Role Serine Protease Skin Sodium-Hydrogen Antiporter Steryl-sulfatase Stratum corneum Structure Surface Thinking Time Topical application Treatment Protocols Urocanic Acid Vitamin D3 Receptor Water Week acid sphingomyelinase alveolar lamellar body chymotrypsin cohesion cytokine day density enzyme activity extracellular glucosylceramidase inhibitor/antagonist keratinocyte keratinocyte differentiation mature animal microbial neonate pH gradient postnatal receptor response skin disorder

项目摘要

DESCRIPTION (provided by applicant): Although the acidic nature of the stratum corneum (SC) has been appreciated for more than a century, both its importance and its origin are poorly understood. Recent studies in adult animals have demonstrated that an acidic SC pH is essential for normal permeability barrier homeostasis and SC integrity and cohesion, and that a neutral SC pH increases the levels of cytokines in the epidermis. An acidic surface pH is achieved in the absence of exogenous mechanisms, such as surface lipids, eccrine gland products, and microbial products, previously thought to be important for SC acidification. Recent studies have shown that three endogenous mechanisms acidify the SC of adult epidermis: 1) free fatty acid generation from phospholipid hydrolysis; 2) a non-energy-dependent, sodium-proton antiporter (NHE1); and 3) urocanic acid generation from histidine. However, studies have shown that the SC of newborn humans has a neutral pH. Over the next several weeks to months the surface pH decreases to adults levels (pH=5.5). As in humans, in a neonatal rat model we have recently shown that the surface pH of newborns is 6.5 to 7.0, and that the surface pH decreases such that by 5-6 days post birth the pH is 5.5 (adult levels). Our studies during the prior funding cycle have shown that activators of PPARa, PPARd, and LXR, stimulate keratinocyte differentiation, permeability barrier homeostasis, and the development of the SC during fetal development. Our preliminary studies have further shown that topical application of ligands of LXR and PPARa accelerates the acidification of the SC in newborn rats. Newborn skin is more susceptible to both external insults and to the development of inflammation than is adult skin. Hypothesis- The SC of newborns has a neutral pH, because one or more of the endogenous mechanisms that are responsible for SC acidification in adults; 1) histidase conversion of histidine to urocanic acid, 2) metabolism of phospholipids to free fatty acids by sPLA2, and/or 3) transport of hydrogen ions into the extracellular space by NHE1, are not yet fully developed in newborn mammal epidermis. With further maturation these pathways develop, and the SC ultimately acidifies, a process that can be accelerated by activation of PPAR alpha, PPAR delta, and LXR. In the neonatal period, this delay in SC acidification results in functional abnormalities, including; a) decreased permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) increased susceptibility to the development of inflammation with a decreased threshold for the development of persistent inflammatory dermatoses. Objectives- 1) To determine the mechanism(s) that lead to postnatal SC acidification. 2) To determine the adverse consequences of a neutral pH on SC function in the newborn. 3) To determine the mechanisms responsible for the a) abnormalities in permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) decreased threshold for the development of inflammation in newborn animals with a neutral SC pH. 4) To determine if activators of PPAR alpha, PPAR delta, and/or LXR accelerate the formation of an acidic SC, the mechanism for this acceleration of acidification, and the functional consequences of such an acceleration.

描述（由申请人提供）：尽管角质层（SC）的酸性性质已被认识超过一个世纪，但其重要性及其起源仍知之甚少。最近在成年动物中的研究已经证明，酸性SC pH对于正常的渗透性屏障稳态和SC完整性和凝聚力是必不可少的，并且中性SC pH增加表皮中细胞因子的水平。酸性表面pH值是在没有外源性机制的情况下实现的，如表面脂质、外分泌腺产物和微生物产物，这些物质以前被认为对SC酸化很重要。最近的研究表明，有三种内源性机制使成人表皮的SC酸化：1）磷脂水解产生游离脂肪酸; 2）非能量依赖性钠质子反向转运蛋白（NHE 1）; 3）组氨酸产生尿刊酸。然而，研究表明，新生儿的SC具有中性pH值。在接下来的几周到几个月内，表面pH值下降到成人水平（pH=5.5）。与人类一样，我们最近在新生大鼠模型中发现，新生儿的表面pH值为6.5至7.0，并且表面pH值降低，出生后5-6天，pH值为5.5（成人水平）。我们在之前的资助周期期间的研究已经表明，PPARa、PPARd和LXR的激活剂刺激角质形成细胞分化、渗透性屏障稳态和胎儿发育期间SC的发育。我们的初步研究进一步表明，局部应用LXR和PPARa的配体加速了新生大鼠SC的酸化。新生儿皮肤比成人皮肤更容易受到外部损伤和炎症的发展。假设-新生儿的SC具有中性pH，因为负责成人SC酸化的一种或多种内源性机制：1）组氨酸转化为尿刊酸的组氨酸酶转化，2）sPLA 2将磷脂代谢为游离脂肪酸，和/或3）NHE 1将氢离子转运到细胞外空间，在新生哺乳动物表皮中尚未完全发育。随着这些途径的进一步成熟，SC最终酸化，这一过程可以通过激活PPAR α、PPAR δ和LXR来加速。在新生儿期，SC酸化的这种延迟导致功能异常，包括：a）渗透性屏障稳态降低，B）SC完整性和凝聚力受损，以及c）对炎症发展的易感性增加，持续性炎性皮肤病发展的阈值降低。目的- 1）确定导致出生后SC酸化的机制。2)确定中性pH值对新生儿SC功能的不良后果。3)为了确定导致具有中性SC pH的新生动物中a）渗透性屏障稳态异常，B）受损的SC完整性和凝聚性，和c）降低的炎症发展阈值的机制。4）为了确定PPAR α、PPAR δ和/或LXR的激活剂是否加速酸性SC的形成，这种加速酸化的机制，以及这种加速的功能后果。