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MMP13 expression and function in allergic inflammation

MMP13在过敏性炎症中的表达和功能

基本信息

批准号：
10054652
负责人：
Jin Mo Park
金额：
$ 40.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-22 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054652
关键词：
Ablation Activins Allergens Allergic Allergic Disease Allergic inflammation Asthma Atopic Dermatitis Attenuated Automobile Driving Biochemical Biological Assay CRISPR/Cas technology Cells Chemicals Complex Cultured Cells Cutaneous Data Development Disease Environmental Risk Factor Enzymes Epithelial Epithelial Cells Event Exhibits Extrinsic asthma Family member Functional disorder Gene Expression Genes Genetic Genetic Transcription Genetic Variation Goals Health High Prevalence Immune response Immune signaling Immune system Immunity Immunization In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Response Investigation Knowledge Lead Light Link Mammalian Cell Matrix Metalloproteinases Mediating Mediator of activation protein Methods Molecular Molecular Target Mus Pathogenicity Pathway interactions Patients Peptide Hydrolases Pharmacology Phenotype Phosphorylation Phosphotransferases Play Process Protein Kinase Proteoglycan Proteomics Recombinant Proteins Research Resistance Resources Role Signal Transduction Skin Stimulus TNFRSF5 gene Therapeutic Tissues Transforming Growth Factor beta United States activin A airway epithelium airway inflammation asthma model base cell type comorbidity cytokine disease heterogeneity disease phenotype effective therapy genome-wide in vivo inhibitor/antagonist keratinocyte loss of function microbial mouse model mutant new therapeutic target patient subsets prevent receptor small molecule small molecule inhibitor socioeconomics therapeutic target transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Atopic dermatitis, asthma, and other allergic diseases pose an enormous socioeconomic burden in the United States and worldwide. Current treatment options for these illnesses are, however, limited in efficacy and lead to symptomatic relief in only subsets of patients. More broadly effective therapies against allergic diseases are desperately needed, yet achieving this imperative requires an advanced understanding of their pathogenic mechanisms and identification of new therapeutic targets. The protein kinase p38α is expressed in most mammalian cell types, and activated by a multitude of immunological signals such as microbial stimuli and cytokines. We have been studying the role of p38α in immunity and inflammation using mice with p38α gene deficiency in various cell types. These efforts led us to discover that p38α in skin epithelial cells played a crucial role in driving atopic dermatitis-like inflammation upon allergen challenge. p38α signaling was found to serve pro-allergic functions via promoting the expression of inflammatory mediators in epithelial cells. We identified the matrix metalloproteinase MMP13 as an epithelial enzyme whose expression was dependent on p38α signaling. Importantly, genetic ablation or pharmacological inhibition of MMP13 suppressed allergic skin and airway inflammation in mice. These findings and other preliminary data suggested the p38α-MMP13 axis as a promising therapeutic target for allergic diseases. In the proposed research, we will seek to validate the importance of the p38α-MMP13 axis in allergen-specific immune sensitization and allergic tissue inflammation. Further, we will perform biochemical analysis of cultured cells and recombinant proteins to establish the molecular pathways underlying p38α-dependent MMP13 expression and MMP13-mediated inflammatory responses. To achieve these goals, we will pursue the following specific aims: to determine the role of epithelial p38α signaling and MMP13 activity in mouse models of atopic dermatitis and asthma (Aim #1); to elucidate the mechanisms linking p38α signaling to MMP13 expression in skin and airway epithelial cells (Aim #2); and to identify the proteolytic targets of MMP13 that contribute to regulating allergic inflammation (Aim #3). The proposed research is expected to reveal the precise pathophysiological functions of p38α and MMP13 during allergic inflammation and the therapeutic potential of targeting the p38α-MMP13 axis in atopic dermatitis and asthma. The molecular mechanisms newly identified in our study will expand the sphere of knowledge about cell signaling in allergic disorders.

项目总结/摘要特应性皮炎、哮喘和其他过敏性疾病在美国造成了巨大的社会经济负担。国家和全世界。然而，目前针对这些疾病的治疗方案在疗效和铅含量方面有限仅在部分患者中缓解症状。针对过敏性疾病的更广泛有效的疗法是迫切需要，但实现这一必要性需要深入了解其致病性，机制和新治疗靶点的识别。蛋白激酶p38α表达于大多数哺乳动物细胞类型，并通过多种免疫信号如微生物刺激和细胞因子本研究利用p38α基因小鼠研究了p38α在免疫和炎症中的作用各种类型的细胞缺乏。这些努力使我们发现，皮肤上皮细胞中的p38α发挥了重要作用。在过敏原激发后驱动特应性皮炎样炎症中的关键作用。p38α信号被发现通过促进上皮细胞中炎症介质的表达而发挥促过敏功能。我们 MMP 13是一种上皮酶，其表达依赖于 p38α信号转导。重要的是，MMP 13的遗传消融或药理学抑制了过敏性皮肤和小鼠的气道炎症。这些发现和其他初步数据表明，p38α-MMP 13轴作为过敏性疾病的有希望的治疗靶点。在拟议的研究中，我们将寻求验证 p38α-MMP 13轴在过敏原特异性免疫致敏和过敏性组织炎症中的重要性此外，我们将对培养的细胞和重组蛋白进行生化分析，以确定 p38α依赖性MMP 13表达和MMP 13介导的炎症反应的分子途径应答为实现这些目标，我们将努力实现以下具体目标：特应性皮炎和哮喘小鼠模型中的上皮p38α信号传导和MMP 13活性（目的#1）; 阐明皮肤和气道上皮细胞中p38α信号与MMP 13表达之间的联系机制（目的 #2）;以及鉴定有助于调节过敏性炎症的MMP 13的蛋白水解靶标（目标#3）。该研究有望揭示p38α和MMP 13的确切病理生理功能特应性皮炎中p38α-MMP 13轴靶向治疗的可能性和哮喘。在我们的研究中新发现的分子机制将扩大知识领域过敏性疾病中的细胞信号