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RabGEF1 in MyD88 signaling, skin immunity, and atopic dermatitis

RabGEF1 在 MyD88 信号传导、皮肤免疫和特应性皮炎中的作用

基本信息

批准号：
9068815
负责人：
Stephen Joseph Galli
金额：
$ 37.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068815
关键词：
Adult Affect Allergens Allergic inflammation Atopic Dermatitis Cell Communication Child Cutaneous Data Development Disease Distant Eczema Family Goals Guanine Nucleotide Exchange Factors Health Healthcare Systems Homeostasis Human IgE Immune Immunity Impairment In Vitro Inflammation Inflammatory Knockout Mice Lead Ligands Lung Mediating Medical Modeling Molecular Morbidity - disease rate Mus Mutation Organ Pathogenesis Pathology Pathway interactions Patients Permeability Phenotype Population Prevention Process Proteins Public Health Receptor Activation Regulation Role Route Serum Signal Pathway Signal Transduction Skin Source Specimen TLR2 gene TLR4 gene TLR5 gene Testing Text Toll-like receptors Work base cost defined contribution economic impact environmental agent immune function in vivo insight keratinocyte mRNA Expression mast cell microbiota microorganism mortality new therapeutic target novel strategies prevent protein expression receptor expression response skin barrier skin disorder skin lesion skin microbiome skin organogenesis socioeconomics

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how the dysregulation of certain keratinocyte functions, by altering the cells' interactions with te skin microbiome, can impair epidermal barrier function, leading to features resembling those of atopic dermatitis (AD) and the development of high serum levels of IgE. Mouse RabGEF1 was discovered as a negative regulator of mast cell activation, and mice globally deficient in RabGEF1 rapidly develop AD-like skin [pathology]. However, conditional deletion of Rabgef1 specifically in mouse keratinocytes is sufficient to drive AD-like skin [pathology] and the development of high levels of serum IgE (as is also seen in AD patients). Moreover, the severe skin disease observed in RabGEF1- deficient mice critically depends on keratinocyte-intrinsic expression of MyD88, an adaptor molecule that mediates signaling by several Toll-like receptors (TLRs). [Expression of RabGEF1 protein] is markedly decreased in lesional skin from patients with AD as compared to healthy skin, whereas MYD88 mRNA expression is significantly increased in lesional skin specimens from AD patients. Since skin is continuously exposed to microorganisms that are a rich source of TLR ligands, we will evaluate to what extent the skin microbiome and keratinocyte TLRs can contribute to the MyD88-dependent AD-like skin [pathology] observed when keratinocytes lack RabGEF1. We will use RabGEF1-deficient mouse and human keratinocytes to analyze in vitro the molecular mechanisms by which RabGEF1 regulates MyD88-dependent signaling pathways. Finally, we will assess how keratinocyte-restricted [complete or partial] reductions in RabGEF1 expression can influence systemic sensitization to allergens via the skin, with the later development of allergic inflammation in distant organs such as the lung. We propose three specific aims to test the General Hypothesis: The development of skin pathology with features of atopic dermatitis, and elevated serum IgE, in RabGEF1-deficient mice reflects the ability of RabGEF1 to maintain skin [barrier and immune] functions by down-regulating pathways initiated by MyD88-dependent signaling in keratinocytes. Aim 1: Define the contributions of MyD88, Toll-like receptors (TLRs), and the skin microflora in the AD-like skin [pathology] induced by keratinocyte-specific Rabgef1 deletion in vivo. Aim 2: Determine the mechanisms by which RabGEF1 negatively regulates MyD88-dependent functional responses and signaling in keratinocytes. Aim 3: Determine the mechanisms by which RabGEF1 deficiency in keratinocytes influences skin sensitization to allergens and the development of the atopic march. This project will clarify how an intrinsic impairment in keratinocyte function due to diminished RabGEF1 can contribute to AD-like skin [pathology]. Ultimately, pursuing such work may enable the discovery of novel therapeutic targets for the prevention or treatment of AD and perhaps other atopic or inflammatory disorders.