Characterizing the Role of Apolipoprotein Receptors in Asthma Pathogenesis

表征载脂蛋白受体在哮喘发病机制中的作用

• 批准号: 8939836
• 负责人: Stewart Levine
• 金额: $ 35.45万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939836
• 关键词: Alveolar Macrophages; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Asthma; Attenuated; Binding; Caring; Cell physiology; Cells; Dendritic Cells; Development; Epithelial Cells; Extrinsic asthma; Goals; Goblet Cells; Granulocyte Colony-Stimulating Factor; Human; Hyperplasia; Immune response; Immunology; Journals; Knockout Mice; Low Density Lipoprotein Receptor; Lung; Mediating; Ovalbumin; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Printing; Production; Pyroglyphidae; Research; Role; VLDL receptor; Vascular Endothelial Cell; airway hyperresponsiveness; airway inflammation; insight; macrophage; novel; receptor

We have identified that apolipoprotein E serves as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma by a low density lipoprotein receptor(LDLR)-dependent mechanism (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). The effects of apoE, which is synthesized by macrophages in the lung, are mediated via binding to LDLRs that are expressed on ciliated airway epithelial cells. This project will utilize apolipoprotein receptor knock-out mice to define the role of other apolipoprotein receptors in modulating the pathogenesis of asthma. Furthermore, the mechanisms by which asthma pathogenesis is modulated by lung apolipoprotein receptors will be characterized. This research has identified (1) a novel role for the very low density lipoprotein receptor in allergic asthma by regulating dendritic cell function. In particular, we have shown that the very low density lipoprotein receptor is expressed by circulating human dendritic cells (DC) and attenuates DC-mediated adaptive immune responses in HDM-induced airway inflammation (Journal of Immunology 2014; 192: 4497) and (2) the interaction between apolipoprotein A-I and its receptor, the ABCA1 transporter, attenuates ovalbumin-induced neutrophilic airway inflammation by suppressing granulocyte colony-stimulating factor production by pulmonary vascular endothelial cells and alveolar macrophages (Am J Respir Cell Mol Biol, 2014, in press).

我们已经确定，载脂蛋白 E 通过低密度脂蛋白受体 (LDLR) 依赖性机制，作为哮喘气道高反应性和杯状细胞增生的内源性负调节剂（载脂蛋白 E 通过 LDL 受体介导的负调节屋尘螨诱导的哮喘）姚X，Fredriksson K，Yu ZX，徐X，Raghavachari N，Keeran KJ，Zywicke GJ， Kwak M、Amar MJ、Remaley AT、Levine SJ。Respir Crit Care Med，2010 年 7 月 9 日。印刷前的电子版）。 apoE 由肺部巨噬细胞合成，其作用是通过与纤毛气道上皮细胞上表达的 LDLR 结合来介导的。 该项目将利用载脂蛋白受体敲除小鼠来确定其他载脂蛋白受体在调节哮喘发病机制中的作用。 此外，还将描述肺载脂蛋白受体调节哮喘发病机制的特征。 这项研究发现 (1) 极低密度脂蛋白受体通过调节树突状细胞功能在过敏性哮喘中发挥新作用。 特别是，我们已经证明，极低密度脂蛋白受体由循环人树突状细胞 (DC) 表达，并减弱 HDM 诱导的气道炎症中 DC 介导的适应性免疫反应（免疫学杂志 2014；192：4497）和（2 ）载脂蛋白 A-I 与其受体（ABCA1 转运蛋白）之间的相互作用，通过抑制卵清蛋白诱导的中性粒细胞气道炎症来减轻肺血管内皮细胞和肺泡巨噬细胞产生粒细胞集落刺激因子（Am J Respir Cell Mol Biol，2014，印刷中）。