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

• 批准号: 8960798
• 负责人: Stephen Joseph Galli
• 金额: $ 38.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/8960798
• 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; Healthcare Systems; Homeostasis; Human; IgE; Immune; Immunity; Impairment; In Vitro; Inflammation; Inflammatory; 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 Receptor 2; Toll-like receptors; Work; base; cost; defined contribution; economic impact; environmental agent; immune function; in vivo; insight; keratinocyte; mRNA Expression; mast cell; microbiome; microorganism; mortality; new therapeutic target; novel strategies; prevent; protein expression; public health relevance; receptor expression; response; skin disorder; skin lesion; socioeconomics

 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.

 描述（由适用提供）：该项目的长期目标是了解某些角质形成细胞功能的失调如何通过改变细胞与TE皮肤微生物组的相互作用来损害表皮屏障功能，从而导致类似于特应性皮炎（AD）的表皮屏障功能以及高血清水平的高血清水平的发育。小鼠rabgef1被发现是肥大细胞激活的负调节剂，而在Rabgef1中全球缺乏的小鼠会迅速发展出类似AD的皮肤[病理学]。然而，在小鼠角质形成细胞中特别删除了RabGeF1的条件缺失足以驱动类似AD的皮肤[病理学]和高水平的血清IgE（正如AD患者中也可以看出）。此外，在Rabgef1缺陷型小鼠中观察到的严重皮肤疾病取决于MyD88的角质形成细胞 - 内膜表达，MyD88是一种辅助分子，它介导了几个Toll样受体（TLR）介导信号传导。 [Rabgef1蛋白的表达]与健康皮肤相比，病变皮肤的皮肤的表达显着降低，而AD患者病变的皮肤标本中MYD88 mRNA表达显着增加。由于皮肤不断暴露于TLR配体的丰富来源的微生物，因此我们将在多大程度上评估皮肤微生物组和角质形成细胞TLR在多大程度上可以促成依赖MyD88的AD类样[病理学]时观察到的，而在角膜生角膜细胞缺乏rabgef1时。我们将使用RABGEF1缺乏小鼠和人角质形成细胞在体外分析Rabgef1调节MYD88依赖性信号通路的分子机制。最后，我们将评估rabgef1表达中角质形成细胞限制的[完全或部分]降低如何通过皮肤影响系统性敏感性，随后在远处的器官（例如肺）中发育过敏感染。我们提出了三个特定的目的，以检验一般假设：在Rabgef1缺陷小鼠中，具有特应性皮炎的特征和血清IgE升高的皮肤病理学的发展，反映了Rabgef1通过下调MyD88依赖性信号来维持皮肤[屏障和免疫]功能的能力[屏障和免疫]功能。 AIM 1：定义MyD88，Toll样受体（TLR）和在体内诱导的AD样皮肤[病理学]中的皮肤菌群的贡献。 AIM 2：确定Rabgef1负调控MyD88依赖性功能响应和信号传导的机制。 AIM 3：确定角质形成细胞中Rabgef1缺乏症影响皮肤对过敏原的敏感性和特应特应特应分月的发育的机制。该项目将阐明由于Rabgef1降低而导致角质形成细胞功能的固有损伤如何有助于类似Ad样的皮肤[病理学]。最终，追求此类工作可能会发现新的治疗靶标，以预防或治疗AD以及其他特应性或炎症性疾病。