CysLT and P2Y Receptors in Lung Inflammation

这项关于扩展支持的提案侧重于 嘌呤能6型受体对小鼠变应原诱导的2型免疫反应的调节作用 呼吸道。P2Y6受体缺失显著增强肺嗜酸粒细胞炎症 和尘螨变应原诱导哮喘模型中2型细胞因子的产生 粉尘螨和链格孢霉菌。在本支助期内， 我们培育了选择性缺失树突状细胞(DC)上的P2Y6受体的小鼠。令人惊讶的是，研究 对这些小鼠的研究表明，DC相关的P2Y6受体仅对 在全球淘汰赛中观察到的保护作用。此外，我们最近的研究表明 慢性支气管炎患者呼吸道上皮祖细胞P2Y6受体的表达 严重的哮喘。未来的研究将在转基因小鼠中使用多种方法的组合 以及人类细胞和样本来检验P2Y6受体信号在上皮细胞中的假说 祖细胞通过调节细胞因子的分泌来控制2型免疫反应 修复和丛生细胞发育。这些研究应该提供有关过程的有价值的信息。 调节2型免疫中的动态平衡，从而改变哮喘的风险和严重程度。 相关性(请参阅说明)： 这项提议试图理解一种被称为P2Y6受体的分子是如何控制 哮喘炎症的严重程度。这些研究应该揭示有助于 哮喘的严重性，并可能导致新的治疗方法。

This proposal for extended support is focused on the mechanisms and cell types by which the purinergic type 6 (P2Y6) receptor regulates the magnitude of allergen-induced type 2 immunity in the respiratory tract. P2Y6 receptor deletion sharply enhances pulmonary eosinophilic inflammation and type 2 cytokine generation in models of asthma induced by allergens from both the dust mite Dermatophagoides farinea and the mold Alternaria alternata. During the current period of support, we developed mice selectively lacking P2Y6 receptors on dendritic cells (DCs). Surprisingly, studies using these mice indicate that DC-associated P2Y6 receptors contribute only modestly to the protective effects observed in the global knockouts. Furthermore, our more recent studies suggest prominent expression of P2Y6 receptors by epithelial progenitor cells in the airways of patients with severe asthma. The studies going forward will use a combination of approaches in transgenic mice and human cells and samples to test the hypothesis that P2Y6 receptor signaling in epithelial progenitors controls type 2 immune responses through regulating cytokine secretion, epithelial repair, and tuft cell development. The studies should provide valuable information on the processes that regulate homeostasis in type 2 immunity that modifies the risk and severity of asthma. RELEVANCE (See instructions): This proposal seeks to understand how a molecule known as the P2Y6 receptor contrils the severity of inflammation in asthma. The studies should reveal potential factors that contribute to asthma severity and could lead to new therapies.