GLP-1R signaling in allergic inflammation

项目摘要 哮喘是美国最常见的慢性疾病之一，是导致哮喘的重要原因。 发病率和死亡率，不仅在美国，而且在世界范围内。在过去的十年里，肥胖已经成为 被认为是哮喘的重要危险因素。流行病学研究揭示了肥胖与 哮喘的发展，哮喘急性发作的风险增加， 哮喘几项研究表明，传统的哮喘治疗在患有哮喘的肥胖人群中降低了疗效。 哮喘我们的新的初步数据表明，通过胰高血糖素样肽-1受体（GLP-1）的信号传导， 1 R）显著抑制肺IL-5和IL-13蛋白和气道嗜酸性粒细胞增多症，在以下两种的鼠体内模型中： a）强适应性免疫开始之前的早期先天性应答，和B）适应性免疫应答 由CD 4 + Th 2细胞驱动。这些初步数据使我们提出假设，GLP-1 R 信号传导是一种负调节剂的早期先天性和适应性免疫反应的模型中， 在高脂饮食诱导的肥胖症期间由链格孢属气道激发产生的哮喘。这项建议会 确定GLP-1 R信号传导如何调节宿主先天免疫细胞和信号传导途径的激活 链格孢菌中的微生物抗原导致肥胖症的过敏性炎症反应。的 拟议的研究是范式转变，因为它们将确定GLP-1 R 信号传导：a）抑制变应原诱导的第2组先天性淋巴样细胞（ILC 2）功能和气道上皮细胞IL-1， B）调节树突细胞迁移和初始T细胞的活化，以及调节T细胞 （Treg）功能。这些拟议的研究具有临床相关性，因为我们将通过以下方式定义潜在机制： 目前FDA批准用于治疗肥胖症和糖尿病的GLP-1 R激动剂可能有效地 治疗变应性气道炎性疾病，例如肥胖情况下的哮喘。拟议 研究将通过定义一种新的机制来推动该领域的发展， 含有过敏原的蛋白酶，如在肥胖症的情况下的链格孢菌。

PROJECT SUMMARY Asthma is one of the most common chronic diseases in the United States and is an important cause of morbidity and mortality, not only in the US, but also worldwide. Over the past decade, obesity has been recognized as an important risk factor for asthma. Epidemiologic studies reveal associations of obesity with the development of asthma, increased risk of asthma exacerbations, and greater risk of hospitalization for asthma. Several studies indicate that conventional asthma therapy has reduced efficacy in obese people with asthma. Our novel preliminary data reveals that signaling through the glucagon-like peptide-1 receptor (GLP- 1R) significantly inhibited lung IL-5 and IL-13 protein and airway eosinophilia in murine in vivo models of both: a) the early innate response prior to the onset of robust adaptive immunity, and b) adaptive immune responses driven by CD4+ Th2 cells. These preliminary data lead us to propose the hypothesis that GLP-1R signaling is a negative regulator of both the early innate and adaptive immune responses in a model of asthma generated by Alternaria airway challenge during high fat diet-induced obesity. This proposal will determine how GLP-1R signaling regulates the activation of host innate immune cells and signaling pathways to the microbial antigens in Alternaria alternata that lead to allergic inflammatory responses in obesity. The proposed studies are paradigm shifting in that they will determine the mechanisms by which GLP-1R signaling: a) inhibits allergen-induced group 2 innate lymphoid cell (ILC2) function and airway epithelial cell IL- 33 production, and b) modulates dendritic cell migration and activation of naive T cells, and T regulatory cell (Treg) function. These proposed studies are clinically relevant in that we will define potential mechanisms by which a GLP-1R agonist, currently FDA approved for the treatment of obesity and diabetes, may be effective in the treatment of allergic airway inflammatory diseases such as asthma in the setting of obesity. The proposed studies will advance the field by defining a novel mechanism that negatively regulates immune responses to the protease containing allergens such as Alternaria alternata in the setting of obesity.