Cell surface LMAN1 as a General Sensor and Negative Regulator of Mannosylated Aeroallergens

生命早期对过敏原的敏化是随后发展为哮喘的危险因素。为 在致敏个体中，哮喘症状的严重程度也与接触过敏原的水平有关。 尽管由过敏原暴露引起的下游适应性免疫反应以及 这些反应与哮喘症状的关系已被很好地理解，对其机制的了解 哪些过敏原最初是在呼吸道中感觉或识别的，以及这些早期事件是如何塑造结果的 疾病的病程仍然很短。该项目的长期目标是描述和理解 LMAN1蛋白作为甘露糖化空气变应原受体的功能。 LMAN1(凝集素，甘露糖结合1)被鉴定为屋尘螨的候选受体。 无偏受体捕获方法。随后的体外生化分析表明，该凝集素可以与 其他无关的过敏原也是如此。LMAN1是一种甘露糖结合凝集素，主要被认为是一种 急诊室、ERGIC和高尔基车厢之间的货物运输机。我们的初步数据显示LMAN1 也存在于细胞表面，表达于树突状细胞(DC)和呼吸道上皮细胞 (AECS)在肺部。我们还有证据表明LMAN1下调免疫反应 抗过敏原，可能是通过调节核因子-kB的活性。在这项提案中，我们试图确定 识别甘露糖音节空气变应原以下调过敏反应是否是一种普遍功能 通过使用生化和细胞结合试验以及通过WT和LMAN1 KO 小鼠至过敏性呼吸道炎症模型。此外，我们的目标是确定分子机制。 LMAN1调节过敏反应的能力。我们将使用WT或LMAN1 KO DC和AEC来 研究LMAN1可能通过四条途径诱导的信号事件，以调节NF-1 KB活动。 了解LMAN1是否可作为变态反应的一般感受器和负调节因子 反应和该受体执行其调节功能的分子机制将提供 为考虑将LMAN1作为潜在的分子药物靶点奠定了基础。如果成功，这将反过来导致 未来研究确认和测试LMAN1靶向疗法调节过敏性呼吸道的疗效 发炎。

Sensitization to allergens early in life is a risk factor for the subsequent development of asthma. For sensitized individuals, severity in asthma symptoms also correlates with the level of exposure to allergens. Although the downstream adaptive immune responses resulting from allergen exposure as well as the relationship of these responses to asthmatic symptoms are well understood, knowledge of the mechanisms by which allergens are initially sensed or recognized in the airway and how such early events shape the resulting disease course are still lacking. The long-term objective of this project is to characterize and understand the function of the protein LMAN1 in serving as a receptor for mannosylated aeroallergens. LMAN1 (Lectin, Mannose Binding 1) was identified as a candidate receptor for house dust mite using an unbiased receptor capture approach. Subsequent in vitro biochemical analysis indicates that this lectin can bind other unrelated allergens as well. LMAN1 is a mannose binding lectin which is primarily recognized to act as a cargo transporter between the ER, ERGIC, and Golgi compartments. Our preliminary data indicates that LMAN1 can also exist on the surface of cells and is expressed on both dendritic cells (DCs) and airway epithelial cells (AECs) in the lung. We additionally have evidence to suggest that LMAN1 downregulates the immune response against allergens, potentially through modulation of NF-kB activity. In this proposal, we seek to determine whether recognition of mannosylated aeroallergens for downregulation of allergic responses is a general function of LMAN1 through the use of biochemical and cellular binding assays and by subjecting WT and LMAN1 KO mice to models of allergic airway inflammation. Furthermore, we aim to determine the molecular mechanisms underlying the ability of LMAN1 to regulate allergic responses. We will use WT or LMAN1 KO DCs and AECs to investigate the signaling events induced through four pathways potentially utilized by LMAN1 to modulate NF- kB activity. Understanding whether LMAN1 can serve as a general sensor and negative regulator of allergic responses and the molecular mechanisms by which this receptor carries out its regulatory function will provide the basis for consideration of LMAN1 as a potential molecular drug target. If successful, this will, in turn, lead to future studies identifying and testing the efficacy of LMAN1-targeted therapies for modulation of allergic airway inflammation.