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感性是随后发生哮喘的危险因素。为了对于过敏个体，哮喘症状的严重程度也与接触过敏原的水平相关。尽管下游的适应性免疫反应是由过敏原暴露以及这些反应与哮喘症状的关系已得到充分理解，通过了解其机制哪些过敏原最初在气道中被感知或识别，以及这些早期事件如何影响最终的结果病程尚缺乏。该项目的长期目标是描述和理解蛋白质 LMAN1 作为甘露糖基化空气过敏原受体的功能。 LMAN1（凝集素、甘露糖结合 1）被鉴定为屋尘螨的候选受体无偏见的受体捕获方法。随后的体外生化分析表明该凝集素可以结合其他不相关的过敏原也是如此。 LMAN1 是一种甘露糖结合凝集素，主要被认为充当 ER、ERGIC 和高尔基室之间的货物运输装置。我们的初步数据表明 LMAN1 也可以存在于细胞表面，并在树突状细胞 (DC) 和气道上皮细胞上表达（AEC）在肺部。我们还有证据表明 LMAN1 下调免疫反应可能通过调节 NF-kB 活性来对抗过敏原。在本提案中，我们力求确定识别甘露糖基化气源性过敏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测定以及对 WT 和 LMAN1 KO 来抑制 LMAN1 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 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 来研究 LMAN1 可能利用的四种途径诱导的信号传导事件来调节 NF- kB 活动。了解LMAN1是否可以作为过敏的通用传感器和负调节因子该受体执行其调节功能的反应和分子机制将提供这是考虑 LMAN1 作为潜在分子药物靶点的基础。如果成功的话，这将反过来导致未来的研究将确定和测试 LMAN1 靶向疗法调节过敏性气道的功效炎。