Epidermal injury and TSLP

表皮损伤和TSLP

• 批准号: 8508647
• 负责人: RAPHAEL KOPAN
• 金额: $ 23.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8508647
• 关键词: Achievement; Adjuvant; Adult; Allergens; Allergic; Allergic Disease; Animal Model; Animals; Asthma; Atopic Dermatitis; Automobile Driving; Birth; Breathing; Bronchiolitis; Cells; Child; Childhood; Childhood Asthma; Collaborations; Data; Defect; Dendritic Cells; Development; Disease; Dose; Eczema; Elements; Environment; Epidermis; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Event; Exhibits; Exposure to; Extrinsic asthma; Germ-Free; Goals; Human; Hygiene; Hypersensitivity; IgE; Immune response; In Vitro; Inbreeding; Incidence; Infant; Inflammation; Inflammatory; Injury; Intervention; Intrinsic factor; Lead; Life; Link; Liquid substance; Lung; Lymphocyte; Maintenance; Modeling; Molecular; Mus; NF-kappa B; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern Recognition; Pattern recognition receptor; Pilot Projects; Predisposition; Production; Recording of previous events; Risk; Risk Factors; Role; Sampling; Serum; Severities; Skin; Source; Suggestion; Symptoms; T-Lymphocyte; Therapeutic Intervention; Umbilical Cord Blood; Water; airborne allergen; airway hyperresponsiveness; airway inflammation; atopy; base; cohort; cytokine; early childhood; human TSLP protein; injured; keratinocyte; microbiome; mouse model; notch protein; novel; novel therapeutic intervention; overexpression; pathogen; prevent; programs; pyroglyphid; response; skin disorder; small molecule

A major goal of the this AADCRC program is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and develop new preventative strategies. In that context, this project aims to investigate means by which to block progression from atopic dermatitis to asthma (often referred to as the atopic march). Patients with a history of severe atopic dermatitis (AD) exhibit a 8-to-10-fold greater incidence of developing asthma. Our recent observations demonstrated that in mice, epidermal-derived thymic stromal lymphopoietin (TSLP) was secreted by AD skin. Moreover, circulating levels of TSLP were sufficient to sensitize the lung airways to inhaled allergens in animals lacking any AD-like pathology, preexisting inflammation, or previous exposure to the allergen. In a pilot study in infants we uncovered a correlation between serum TSLP and aeroallergens. Based on these observations in mice and humans, we hypothesize the following mechanism for the atopic march. (1) Epidermal defect/injury during early childhood is sensed by an unknown mechanism that initiates production of TSLP in keratinocytes; (2) keratinocytes secrete TSLP into the serum. (3) Subsequently, circulating TSLP facilitates Th2 immune responses by dendritic cells and T-cells towards innocuous allergens (inhaled or introduced epicutaneously); and (4) this exaggerated adaptive Th2 response results in hypersensitivity to aeroallergens and consequent allergic asthma. We further hypothesize that interrupting some of these events in a model organism will lead to strategies for blocking the development of allergic disease and asthma in humans. To achieve this goal, we propose the to (I) examine how epidermal differentiation/barrier formation defects (intrinsic factors) as well as allergen or pathogens (extrinsic factor(s)) drive TSLP overexpression; (II) with the help of Cores B and C ask how TSLP secretion is regulated by human skin and lung cells in vitro and in patients. Next, (III) we will ask if we can blunt the effects of TSLP in the serum with small molecule adjuvants capable of manipulating the immune responses and (IV) analyze the contribution of the skin microbiome to the maintenance of skin barrier, TSLP expression, and airway hyper sensitivity. Finally, (V) we will confirm TSLP as a risk factor for asthma in a birth cohort (URECA) and, in collaboration with project1, compare its role in an RSV bronchiolitis in early life cohort (RBEL). Achievement of these aims will open up novel therapeutic approach to prevent asthma development in AD patients.

该AADCRC计划的主要目标是定义上皮细胞屏障在 哮喘和过敏性疾病的发病机理，并制定新的预防策略。在这种情况下，这个 项目旨在调查能够阻止特应性皮炎到哮喘进展的方法（通常 称为特征游行）。患有严重特应性皮炎（AD）病史的患者表现出8至10倍 发生哮喘的发生率更大。我们最近的观察结果表明，在小鼠表皮衍生的小鼠中 AD皮肤分泌胸腺基质淋巴细胞增多素（TSLP）。此外，TSLP的循环水平 足以使肺气道敏感到缺乏任何类似广告样病理学的动物中吸入过敏原， 先前存在的炎症或先前暴露于过敏原。在对婴儿的试点研究中，我们发现了 血清TSLP和气凝胶之间的相关性。基于在小鼠和人类中的这些观察结果，我们 假设针对特应特征游行的以下机制。 （1）儿童早期表皮缺陷/伤害 通过一种未知的机制来感知，该机制启动角质形成细胞中TSLP的产生。 （2）角质形成细胞 将TSLP分泌到血清中。 （3）随后，循环TSLP通过 树突状细胞和T细胞朝着无害的过敏原（表皮上吸入或引入）； （4）这个 夸张的自适应TH2反应导致对气凝胶的高敏性和随之而来的过敏性 哮喘。我们进一步假设，中断模型生物体中的某些事件将导致 阻止人类过敏性疾病和哮喘发展的策略。为了实现这一目标，我们 提出TO（i）检查表皮分化/屏障形成缺陷（内在因素）以及 过敏原或病原体（外部因素（S））驱动TSLP过表达； （ii）在核心B和C的帮助下问 在体外和患者中，TSLP分泌如何受人皮肤和肺细胞的调节。接下来，（iii）我们会问是否 我们可以用能够操纵该的小分子佐剂在血清中TSLP的影响 免疫反应和（iv）分析皮肤微生物组对维持皮肤的贡献 屏障，TSLP表达和气道超灵敏度。最后，（v）我们将确认TSLP是 出生队列中的哮喘（URECA），并与Project1合作，比较其在RSV细支气管炎中的作用 在早期人生队列（RBEL）中。这些目标的实现将开辟新颖的治疗方法以防止 AD患者的哮喘发育。