Nature of mamalian Cutaneous Permeablilty Barrier

哺乳动物皮肤渗透屏障的性质

基本信息

批准号：
7648253
负责人：
Peter M Elias
金额：
$ 34.67万
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：
1979
资助国家：
美国
起止时间：
1979-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7648253
关键词：
Accounting Address Adult Adverse effects Affect Algorithms Alleles Allergens Allergic rhinitis Animal Model Anti-Retroviral Agents Antigens Apoptosis Aspartic Endopeptidases Asthma Atopic Dermatitis Automobile Driving Biochemical Bullous Congenital Ichthyosiform Erythroderma Calcineurin inhibitor Child Chronic Crowding Cutaneous Defect Dermatitis Deterioration Disease Economic Burden Environmental Risk Factor Enzymes Etiology European Exposure to Family Figs - dietary Functional disorder Genetic Engineering Genetic Polymorphism Genotype Glucocorticoids Goals Haptens Homeostasis Human Humidity Hydration status Hyperactive behavior Ichthyoses Ichthyosis Vulgaris IgE IgE Receptors Immunologics Incidence Infant Inflammation Inflammatory Inherited Intervention Keratoderma Kininogenase Life Link Lipids Maintenance Mites Molecular Abnormality Movement Mus Mutation Nature Nonbullous congenital ichthyosiform erythroderma Oxazolone Pathogenesis Pathway interactions Patients Penetration Pepstatins Peptide Hydrolases Peripheral Permeability Pharmaceutical Preparations Phenotype Prevalence Production Protease Inhibitor Proteins Psychological Stress Pyroglyphidae Quality of life RU-486 Recruitment Activity Relative (related person)Role Route S100 Proteins Serine Protease Serine Proteinase Inhibitors Severities Simulate Single Nucleotide Polymorphism Skin Soaps Stratum corneum Structural Protein Structure Subgroup Surface Syndrome Tail Therapeutic Therapeutic Intervention Trypsin Inhibitors Water Wild Type Mouse Work acquired factor alveolar lamellar body analog antalarmin atopy base clinical phenotype cytokine environmental stressor extracellular filaggrin gain of function improved kindred loricrin loss of function mutation mouse model pepstatin premature prevent public health relevance receptor expression skin disorder standard care stressor surfactant transglutaminase 1 uptake

项目摘要

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is an increasingly common disease of uncertain etiology. Whereas much prior work has focused on an immunologic etiopathogenesis, recent linkage studies show that inherited mutations in a stratum corneum (SC) structural protein, filaggrin (FLG) occur in up to 30 percent of AD patients of European origin. In addition, several AD kindreds have now been described with putative gain-of-function polymorphisms in SC chymotryptic enzyme Kallikrein 7 (Klk7) and loss-of-function mutations in SPINK5, which encodes a key epidermal serine protease (SP) inhibitor, lymphoepithelial Kazal-type trypsin inhibitor (LEKTI). Together, these studies suggest that a primary abnormality in SC structure and function allows antigen access, thereby driving downstream immunologic phenomena in AD. Yet single-allele and even double-allele FLG mutations may only produce a milder, scaling disorder, ichthyosis vulgaris (IV). Our first hypothesis, therefore, is that more than one mutation may be required to transform IV into AD, and additive mutations that effect barrier function could predict convergent or divergent pathophysiological mechanisms. Yet, mutations alone may not suffice to produce AD, but superimposition of exogenous stressors, such as a decreased relative humidity (RH), repeated use of high pH surfactants, and/or sustained psychological stress (PS), could aggravate inherited structural/enzyme defects. All of these stressors are known to both disturb barrier function in normal skin, and to trigger or exacerbate AD. Their role in AD provocation will be assessed in two animal models of AD with defined, underlying SC defects. Then, we will assess the pathophysiological mechanisms leading to AD in fully genotyped humans with IV and AD, with FLG-/- plus one or more of the protease/antiprotease mutations. Further mechanistic studies will then be assessed in the animal models, including particularly the role of additive increases in pH provoking elevations in SP, with divergent, downstream pathways leading to barrier dysfunction, abnormal SC integrity, and primary cytokine release. Finally, based upon the dominant, operative pathophysiological mechanism, we will assess the potential utility of systemic and/or topical therapies that specifically target these pathomechanisms. PUBLIC HEALTH RELEVANCE. Atopic Dermatitis (AD) is an increasingly common inflammatory skin condition, predominantly affecting infants and children but its prevalence in adults is also increasing. AD not only places an enormous economic burden, but it also exacts an often-devastating toll on the quality of life of patients and families. We will be addressing the pathogenic role of inherited and acquired factors that could converge to degrade barrier function, allowing uptake of allergens leading to disease provocation. Because the current standard treatment of AD with glucocorticoids and calcineurin inhibitors is accompanied by significant side effects, alternate approaches, based upon correcting the primary barrier abnormality, could provide safer therapeutic alternatives. Because AD frequently represents the first step in the `atopic march,' which denotes the tendency to progress from initial AD in infants to include asthma and/or allergic rhinitis, therapy that corrects barrier function could also reduce the likelihood and/or severity of the `atopic march.'

描述（由申请人提供）：特应性皮炎（AD）是一种不确定病因的日益常见的疾病。尽管许多先前的工作都集中在免疫病理学上，但最近的连锁研究表明，在欧洲起源的AD患者中，遗传性角膜（SC）结构蛋白（SC）结构蛋白（FLG）的遗传突变发生。此外，现在已经描述了几种广告中的广告含量，在SC辣椒酶Kallikrein 7（KLK7）和Spink5中的功能丧失突变中，编码关键的表皮丝蛋白蛋白酶（SP）抑制剂，淋巴细胞运动kazalib-typsinpe TrypsInsIntient（pepsitienti）（pepsitientient）（spink）5中的功能收益。总之，这些研究表明，SC结构和功能的主要异常允许抗原进入，从而在AD中推动下游免疫学现象。然而，单位物质甚至双等位基因FLG突变可能只会产生更温和的缩放障碍，鱼质福克利（IV）。因此，我们的第一个假设是，将IV转化为AD可能需要多个突变，而影响屏障功能的添加剂突变可以预测收敛或发散的病理生理机制。然而，单独的突变可能不足以产生AD，而是外源应激源的叠加，例如相对湿度降低（RH），重复使用高pH表面活性剂和/或持续的心理压力（PS），可能会加剧遗传的结构/酶缺损。已知所有这些应力既干扰正常皮肤的屏障功能，又会触发或加剧AD。它们在AD挑衅中的作用将在两个具有定义的，基本的SC缺陷的AD动物模型中进行评估。然后，我们将评估带有IV和AD的完全基因分型人类中AD的病理生理机制，具有FLG - / - 加上一个或多个蛋白酶/抗蛋白酶突变。然后，将在动物模型中评估进一步的机械研究，包括尤其是添加剂增加SP的添加剂增加的作用，并具有不同的下游途径，导致屏障功能障碍，异常SC完整性和原发性细胞因子释放。最后，基于主要的，手术的病理生理机制，我们将评估专门针对这些病理机理的全身和/或局部疗法的潜在效用。公共卫生相关性。特应性皮炎（AD）是一种日益常见的炎症性皮肤状况，主要影响婴儿和儿童，但其成人的患病率也在增加。广告不仅承受着巨大的经济负担，而且还对患者和家庭的生活质量造成了巨大的损害。我们将解决遗传和获取因素的致病作用，这些因素可能会融合到降解屏障功能，从而摄取导致疾病引起的过敏原。由于目前用糖皮质激素和钙调神经蛋白抑制剂对AD进行的标准处理伴随着重要的副作用，因此基于纠正主要屏障异常的替代方法可以提供更安全的治疗替代方法。因为AD经常代表“特应游行”的第一步，这表示从婴儿初始AD到包括哮喘和/或过敏性鼻炎的趋势，因此纠正屏障功能的治疗也可以降低“原子游行”的可能性和/或严重性。