CysLT and P2Y Receptors in Lung Inflammation

肺部炎症中的 CysLT 和 P2Y 受体

• 批准号: 10321255
• 负责人: Joshua A Boyce
• 金额: $ 53.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321255
• 关键词: Allergens; Alternaria; Asthma; Cells; Dendritic Cells; Dermatophagoides; Development; Epithelial; Generations; Homeostasis; Human; Immune response; Immunity; Inflammation; Instruction; Knock-out; Lead; Lung; Molds; Mus; Patients; Process; Pulmonary Inflammation; Receptor Signaling; Respiratory System; Risk; Sampling; Severities; Testing; Transgenic Mice; asthma model; cell type; cytokine; eosinophilic inflammation; epithelial repair; epithelial stem cell; novel therapeutics; progenitor; protective effect; pyroglyphid; receptor

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.

这项扩展支持的建议集中于机制和细胞类型 嘌呤能6型（P2Y6）受体调节过敏原诱导的2型免疫的大小 呼吸道。 P2Y6受体缺失急剧增强肺嗜酸性炎症 和2型细胞因子产生在过敏原引起的哮喘模型的模型中 Dermatophagoides farinea和霉菌替代品。在当前的支持期间， 我们在树突状细胞（DCS）上有选择地开发了缺乏P2Y6受体的小鼠。令人惊讶的是，研究 使用这些小鼠表明与DC相关的P2Y6受体仅适度贡献 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 P2Y6受体通过上皮祖细胞在患者气道中的显着表达 严重的哮喘。未来的研究将使用转基因小鼠的方法组合 人类细胞和样品以检验上皮中P2Y6受体信号传导的假设 祖细胞通过调节细胞因子分泌，上皮来控制2型免疫反应 修复和簇细胞的发育。研究应提供有关过程的宝贵信息 调节2型免疫力的体内平衡会改变哮喘的风险和严重程度。 相关性（请参阅说明）： 该提议试图了解一个称为P2Y6受体的分子如何扭曲 哮喘炎症的严重程度。研究应揭示有助于 哮喘的严重程度可能导致新的疗法。

项目成果

Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation.

• DOI: 10.4049/jimmunol.1000104
• 发表时间: 2010-05-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Simarro M;Giannattasio G;De la Fuente MA;Benarafa C;Subramanian KK;Ishizawar R;Balestrieri B;Andersson EM;Luo HR;Orduña A;Boyce J;Anderson P
• 通讯作者: Anderson P

Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.

• DOI: 10.1084/jem.20091240
• 发表时间: 2009-10-26
• 期刊: The Journal of experimental medicine
• 作者: Paruchuri S;Tashimo H;Feng C;Maekawa A;Xing W;Jiang Y;Kanaoka Y;Conley P;Boyce JA
• 通讯作者: Boyce JA

Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms.

• DOI: 10.1038/mi.2017.99
• 发表时间: 2018-05
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Yamaguchi M;Samuchiwal SK;Quehenberger O;Boyce JA;Balestrieri B
• 通讯作者: Balestrieri B