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Allergic Pulmonary Inflammation Through the Dectin-2 Pathway

通过 Dectin-2 途径发生的过敏性肺部炎症

基本信息

批准号：
8612049
负责人：
Nora Amanda Barrett
金额：
$ 40.55万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8612049
关键词：
Adaptor Signaling Protein Address Allergens Allergic Allergic inflammation Antibodies Aspergillus fumigatus Asthma C Type Lectin Receptors Cell physiology Cells Data Dendritic Cells Dendritic cell activation Dermatophagoides farinae Dermatophagoides pteronyssinus Development Disease Environmental Exposure Extrinsic asthma Functional disorder Gene Mutation Generations Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Human Hypersensitivity ITGAX gene Immune Immune response Immunity Immunologic Receptors Inflammatory Interleukin-1 Interleukin-6 Knockout Mice Leukotriene Production Ligands Lipids Mediating Mitogen-Activated Protein Kinases Molds Molecular Mouse Strains Mus Mutation Myelogenous Pathway interactions Patients Pattern recognition receptor Phase Pneumonia Polysaccharides Prevention strategy Production Pyroglyphidae Recruitment Activity Regulation Research Personnel Role Signal Transduction Small Interfering RNA Staging TNF gene Therapeutic Therapeutic Intervention autocrine base clinically relevant conditioning cysteinyl leukotriene receptor cysteinyl leukotriene receptor 2 cysteinyl-leukotriene cytokine human TSLP protein immunopathology in vivo Model insight interleukin-23 leukotriene-C4 synthase lymph nodes monocyte mouse dectin-2 novel paracrine public health relevance pyroglyphid response tool treatment strategy

项目摘要

This application to support a new early stage investigator focuses on the role of Dectin-2 in the pathophysiology of allergen-induced pulmonary inflammation. We have previously discovered that the dendritic cell (DC) C-type lectin receptor Dectin-2 is activated by glycans found in common, clinically relevant, allergens such as the house dust mite (HDM) species Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus (Dp) and the mold Aspergillus fumigatus (Af). Activation of Dectin-2 by Df, Dp, or Af triggers production of pro-inflammatory cytokines (IL-23, IL-1 beta, IL-6, and TNF-¿) and cysteinyl leukotrienes (cys- LTs). Cys-LTs produced by such activation condition DCs in an autocrine fashion to promote Th2 immune responses, via the type 1 receptor for cysteinyl leukotrienes (cys-LTs), CysLT1R. CysLT1R signaling and Th2 priming on DCs are negatively regulated by the type 2 receptor for cys-LTs, CysLT2R. These data suggest that Th2 immunity to allergens can be finely regulated by signaling from cys-LTs. The current proposal will use mouse strains with genetic mutations in classical and novel CysLTRs to understand how they influence DC activation and Th2 priming to native allergens (Aim 1). Human monocyte-derived DCs will also be assessed by using siRNA-mediated knockdown of CysLTRs. We have identified that Dectin-2 has a critical role in triggering allergic inflammation during the challenge phase and Aim 2 of the current proposal will use in vivo models of HDM sensitization and challenge to understand the role of Dectin-2 and DCs in the elicitation phase. Greater than 50% of asthma is attributable to allergy and HDM is the most common allergen worldwide. Therefore, understanding how Dectin-2 mediates sensitization and propagation of HDM-triggered immunopathology offers a MAJOR potential therapeutic benefit.

这个应用程序支持一个新的早期阶段的调查员侧重于Dectin-2的作用