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.

项目概要/摘要特应性皮炎、哮喘和其他过敏性疾病给美国带来了巨大的社会负担然而，目前针对这些疾病的治疗方案的疗效和领先性有限。更广泛有效的治疗方法是针对过敏性疾病。迫切需要，但实现这一迫切需要需要对其致病性有深入的了解蛋白激酶 p38α 在大多数细胞中表达。哺乳动物细胞类型，并被多种免疫信号激活，例如微生物刺激和我们一直在使用带有 p38α 基因的小鼠研究 p38α 在免疫和炎症中的作用。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。发现 p38α 信号在过敏原刺激后驱动特应性皮炎样炎症中发挥关键作用。通过促进上皮细胞中炎症介质的表达来发挥促过敏功能。鉴定出基质金属蛋白酶 MMP13 是一种上皮酶，其表达依赖于重要的是，MMP13 的基因消除或药理抑制可抑制过敏性皮肤。这些发现和其他初步数据表明 p38α-MMP13 轴。作为过敏性疾病的一个有前途的治疗靶点，在拟议的研究中，我们将寻求验证。 p38α-MMP13 轴在过敏原特异性免疫敏化和过敏性组织炎症中的重要性。此外，我们将对培养细胞和重组蛋白进行生化分析，以确定分子基础途径p38α依赖性MMP13表达和MMP13介导的炎症为了实现这些目标，我们将追求以下具体目标：确定的作用。特应性皮炎和哮喘小鼠模型中的上皮 p38α 信号转导和 MMP13 活性（目标 1）；阐明皮肤和气道上皮细胞中 p38α 信号传导与 MMP13 表达的联系机制（目标 #2)；并确定有助于调节过敏性炎症的 MMP13 蛋白水解靶标（目标 #3）。该研究有望揭示p38α和MMP13的精确病理生理功能过敏性炎症期间的研究以及靶向 p38α-MMP13 轴在特应性皮炎中的治疗潜力我们的研究中新发现的分子机制将扩大知识范围。关于过敏性疾病中的细胞信号传导。