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

细胞表面 LMAN1 作为甘露糖基化空气过敏原的通用传感器和负调节器

• 批准号: 10521583
• 负责人: Justine Tiglao Tigno-Aranjuez
• 金额: $ 39.18万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521583
• 关键词: Adoptive Transfer; Adrenal Cortex Hormones; Affect; Agonist; Allergens; Allergic; Allergic inflammation; Antibody Formation; Asthma; Attenuated; Binding; Biochemical; Biological Assay; Biological Products; Bone Marrow; Cell Line; Cell surface; Chimera organism; Chronic; Cytoplasmic Tail; Data; Dendritic Cells; Development; Disease; Dose; Down-Regulation; EMSA; Engineering; Epithelial Cells; Event; Exposure to; Extrinsic asthma; Flow Cytometry; Future; Golgi Apparatus; Histopathology; Immune response; In Vitro; Individual; Inflammatory; Inflammatory Response; Inhalation; Knockout Mice; Knowledge; Laboratories; Lead; Lectin; Life; Ligands; Luciferases; Lung; Mannose; Mannose Binding Lectin; Mediator of activation protein; Medicine; Modeling; Molecular; NF-kappa B; Pathway interactions; Persons; Phenotype; Play; Process; Production; Proteins; Pyroglyphidae; Quality of life; Regulation; Reporting; Respiratory Tract Infections; Risk Factors; Role; Severities; Shapes; Signal Transduction; Structure; Surface; Symptoms; T cell response; Testing; Therapeutic; Western Blotting; adaptive immune response; airborne allergen; airway epithelium; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; allergic response; asthma model; asthmatic; base; biological adaptation to stress; cytokine; design; efficacy testing; endoplasmic reticulum stress; in vivo; interest; molecular drug target; mutant; novel; novel therapeutics; prevent; protein function; receptor; response; sensor; symptom management; targeted treatment; therapeutic target; therapy development; valosin-containing protein

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.

在生命早期对过敏原过敏是随后发生哮喘的危险因素。为 在致敏个体中，哮喘症状的严重程度也与暴露于过敏原的水平相关。 尽管由过敏原暴露引起的下游适应性免疫应答以及 这些反应与哮喘症状的关系已经很好地理解，通过以下机制的知识 最初在气道中感知或识别哪些过敏原以及这些早期事件如何形成结果 病程尚不完善。该项目的长期目标是描述和了解 蛋白质LMAN 1在充当甘露糖基化的空气过敏原的受体中的功能。 LMAN 1（凝集素，甘露糖结合1）被鉴定为屋尘螨的候选受体，使用 无偏受体捕获方法。随后的体外生化分析表明，这种凝集素可以结合 其他不相关的过敏原。LMAN 1是一种甘露糖结合凝集素，其主要被认为是一种甘露糖结合凝集素。 ER、ERGIC和高尔基体之间的货物转运蛋白。我们的初步数据表明，LMAN 1 也可存在于细胞表面，并在树突状细胞（DC）和气道上皮细胞上表达 （AECs）在肺中。我们还有证据表明LMAN 1下调免疫反应， 抗过敏原，可能通过调节NF-κ B活性。在这份提案中，我们试图确定 识别甘露糖基化的吸入性过敏原下调过敏反应是否是一种普遍的功能 通过使用生物化学和细胞结合测定，并通过使WT和LMAN 1 KO 小鼠过敏性气道炎症模型。此外，我们的目标是确定分子机制 LMAN 1调节过敏反应的能力。我们将使用WT或LMAN 1 KO DC和AEC， 研究通过LMAN 1可能利用的四种途径诱导的信号传导事件，以调节NF-κ B。 kB活动 了解LMAN 1是否可以作为过敏反应的一般传感器和负调节器 反应和该受体执行其调节功能的分子机制将提供 LMAN 1作为潜在分子药物靶点的考虑基础。如果成功，这将反过来导致 未来的研究确定和测试LMAN 1靶向治疗调节过敏性气道的疗效 炎症