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

基本信息

批准号：
10654031
负责人：
Justine Tiglao Tigno-Aranjuez
金额：
$ 38.11万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
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/10654031
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 Lectin Life Ligands Luciferases Lung Mannose Mannose Binding Lectin Mediator Medicine Modeling Molecular NF-kappa B Pathway interactions Persons Phenotype Play Process Production Proteins Pyroglyphidae Quality of life Recommendation 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 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

项目摘要

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.

生命早期对过敏原的敏化是随后哮喘发育的危险因素。为了敏感的个体，哮喘症状的严重程度也与暴露水平有关。尽管过敏原暴露引起的下游自适应免疫反应以及这些反应对哮喘症状的关系是充分理解的，了解机制的知识最初在气道中感知或识别哪种过敏原，以及这样的早期事件如何影响由此产生的疾病病程仍然缺乏。该项目的长期目标是表征和了解蛋白LMAN1在充当甘露糖基化气溶胶受体中的功能。 LMAN1（凝集素，甘露糖结合1）被鉴定为使用一个房屋尘螨的候选受体公正的受体捕获方法。随后的体外生化分析表明，该凝集素可以结合其他无关的过敏原。 lman1是一种甘露糖结合凝集素，主要被认为是 ER，Ergic和Golgi隔室之间的货物转运蛋白。我们的初步数据表明LMAN1 也可以在细胞表面存在，并在树突状细胞（DC）和气道上皮细胞上表达（AEC）在肺中。我们还有证据表明LMAN1下调了免疫反应针对过敏原，可能通过调节NF-KB活性。在此提案中，我们试图确定是否识别甘露糖基化的气溶剂以下调过敏反应是一般功能通过使用生化和细胞结合测定法以及对WT和LMAN1 KO进行的LMAN1的使用小鼠到过敏性气道炎症模型。此外，我们旨在确定分子机制 LMAN1调节过敏反应的能力的基础。我们将使用WT或LMAN1 KO DC和AEC进行研究通过LMAN1潜在利用的四个途径引起的信号事件来调节NF- KB活动。了解LMAN1是否可以用作过敏性的一般传感器和负面调节剂该受体执行其调节功能的反应和分子机制将提供将LMAN1视为潜在的分子药物靶标的基础。如果成功的话，这将导致未来的研究确定和测试LMAN1靶向疗法的疗效用于调节过敏性气道炎。