MMP13 expression and function in allergic inflammation

项目摘要/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。 美国和世界各地。然而，目前这些疾病的治疗方案在疗效和含铅量方面都是有限的。 仅在部分患者中有症状缓解。更广泛有效的治疗过敏性疾病的方法是 然而，要实现这一迫切需要，需要对它们的致病机理有更深入的了解 新的治疗靶点的确定和作用机制。蛋白激酶p38α在大多数组织中表达。 哺乳动物细胞类型，并由多种免疫信号激活，如微生物刺激和 细胞因子。我们一直在利用携带p38α基因的小鼠研究p38α在免疫和炎症中的作用。 各种细胞类型的缺陷。这些努力使我们发现皮肤上皮细胞中的p38α发挥了 在过敏原激发下驱动特应性皮炎样炎症中的关键作用。P38α信号转导被发现 通过促进上皮细胞中炎症介质的表达起到促过敏作用。我们 基质金属蛋白酶MMP13是一种上皮酶，其表达依赖于 P38α信号转导。重要的是，MMP13的基因消融或药物抑制可抑制过敏皮肤 和小鼠的呼吸道炎症。这些发现和其他初步数据表明，p38α-MMP13轴 作为治疗过敏性疾病的有希望的靶点。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增敏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 P38α依赖的基质金属蛋白酶13表达及其介导的炎症反应的分子途径 回应。为了实现这些目标，我们将追求以下具体目标：确定 特应性皮炎和哮喘小鼠模型中上皮p38α信号和基质金属蛋白酶13活性(目标1)； 阐明p38α信号与皮肤和呼吸道上皮细胞MMP13表达的关系(目的) #2)；以及确定有助于调节过敏性炎症的MMP13的蛋白降解靶点(目标#3)。 这项拟议的研究有望揭示p38α和MMP13的确切病理生理功能。 特应性皮炎的过敏性炎症过程及靶向p38α-MMP13轴的治疗潜力 还有哮喘。我们研究中新发现的分子机制将扩大我们的知识范围 关于过敏性疾病中的细胞信号。

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.