Mechanisms of non-IgE Mast Cell Activation by Environmental Particulates

环境颗粒物激活非 IgE 肥大细胞的机制

基本信息

批准号：
10424529
负责人：
Jared Michael Brown
金额：
$ 52.26万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10424529
关键词：
Adverse effects Air Pollution Allergens Arrestins Autoimmunity Blood Vessels CD34 gene Cardiovascular Diseases Cardiovascular system Cell Degranulation Cell physiology Cells Chronic Communication Cytoplasmic Granules Data Disease Disease Outcome Engineering Environmental Exposure Environmental Health Etiology Exocytosis Funding G-Protein-Coupled Receptors Genes Genetic Glycolysis Goals Human Hybrids Hypersensitivity IgE Immune response In Vitro Inflammation Inflammatory Innate Immune System Lung Lung diseases Malignant Neoplasms Mass Spectrum Analysis Mediating Mouse Strains Mucous Membrane Mus Natural Immunity Nerve Degeneration Nervous system structure Outcome Oxidation-Reduction Oxides Particulate Particulate Matter Pathogenicity Pathologic Pathology Pathway interactions Patients Phase Physiological Post-Translational Protein Processing Predisposition Production Proteins Proteomics Pulmonary Heart Disease Regulation Research Role Sensory Signal Transduction Silicon Dioxide Silver Sulfhydryl Compounds Surface System TXN gene TXNIP gene Testing Tissues Toxic Environmental Substances Up-Regulation Urticaria Work Xenobiotics adaptive immunity adverse outcome animal data anti-IgE arm base blood glucose regulation crystallinity cytokine environmental particulate first responder genome wide association study glucose metabolism granule cell immune system function immunoregulation mast cell nanomaterials nanoparticle novel omalizumab particle response sensor stem cells tool transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Inflammation is recognized as a major underlying mechanism for a number of diseases with an environmental etiology that have serious pathologic outcomes such as autoimmunity, cancer, cardiovascular disease, lung disease, neurodegeneration as examples. Mast cells represent a major sensory arm of the body's innate immune system by functioning as environmental `sensors' to communicate with other physiological and/or immune responses due to their widespread tissue presence at mucosal surfaces, near blood vessels and the nervous system. Through funding from R01 ES019311, we have begun to unravel novel mechanisms of non- IgE mast cell activation that contribute to inflammation. While mast cells are implicated as pathogenic in a number of diseases beyond allergy little is known on mechanisms and even less is known regarding how environmental toxicants trigger mast cell responses that contribute to these disease outcomes. Therefore, our overarching research goal has been focused on delineating the role of mast cells in environmental health through better understanding of their role as first responders in environmental insult, resulting effects on innate and adaptive immunity, and their communication with other cells and physiological systems. Our research has uncovered novel non-IgE mediated mechanisms of mast cell activation driven by particulates (e.g. nanoparticles, air pollution particulate matter, silica, etc) that contributes to adverse outcomes in the pulmonary and cardiovascular system. In addition, through genome wide association studies using the hybrid mouse diversity panel as well as transcriptomics studies we have uncovered novel genetic regulation of non-IgE mast cell activation driven by particulates. In particular, we have found a regulatory role for thioredoxin interacting protein (Txnip) in non-IgE mast cell activation. In this proposal, we will investigate both redox-independent and -dependent Txnip regulation of mast cell activation by environmental particulates (nanoparticles and ambient particulate matter) and its influence on G protein-coupled receptors, glycolysis, redox regulation and granule exocytosis. In addition, we will investigate the role of Txnip using mast cells from patients with chronic idiopathic urticaria (a mast cell activation disorder largely driven by non-IgE mechanisms and which is thought to be triggered by environmental exposures). Our overall goal is to delineate the role mast cells in environmental health through better understanding of their role as first responders in environmental insult, their activation by particulates and novel mechanisms of non-IgE activation that contributes to disease outcomes.

项目概要炎症被认为是许多与环境有关的疾病的主要潜在机制。具有严重病理结果的病因，例如自身免疫、癌症、心血管疾病、肺病疾病，神经退行性疾病为例。肥大细胞代表身体先天的主要感觉臂免疫系统作为环境“传感器”与其他生理和/或免疫反应是由于它们广泛存在于粘膜表面、血管附近和周围的组织中神经系统。通过 R01 ES019311 的资助，我们已经开始解开非 IgE 肥大细胞激活导致炎症。虽然肥大细胞被认为具有致病性除了过敏以外，还有许多疾病的机制我们知之甚少，更不知道它是如何发生的。环境毒物会触发肥大细胞反应，从而导致这些疾病的结果。因此，我们的总体研究目标集中于描绘肥大细胞在环境健康中的作用通过更好地了解他们作为环境侵害第一响应者的角色，从而对先天造成的影响和适应性免疫，以及它们与其他细胞和生理系统的通讯。我们的研究有发现了由颗粒驱动的肥大细胞激活的新的非 IgE 介导机制（例如纳米颗粒、空气污染颗粒物、二氧化硅等）会导致肺部不良后果和心血管系统。此外，通过使用杂交小鼠进行全基因组关联研究多样性小组以及转录组学研究，我们发现了非 IgE 肥大的新遗传调控由颗粒驱动的细胞激活。特别是，我们发现了硫氧还蛋白相互作用的调节作用蛋白（Txnip）在非 IgE 肥大细胞激活中的作用。在本提案中，我们将研究氧化还原无关和 -环境颗粒物（纳米颗粒和环境颗粒物）对肥大细胞活化的依赖性 Txnip 调节颗粒物）及其对 G 蛋白偶联受体、糖酵解、氧化还原调节和颗粒的影响胞吐作用。此外，我们将使用来自慢性病患者的肥大细胞来研究 Txnip 的作用。特发性荨麻疹（一种肥大细胞活化障碍，主要由非 IgE 机制驱动，被认为是由环境暴露触发）。我们的总体目标是描绘肥大细胞在通过更好地了解他们作为环境侵害第一响应者的角色，他们的环境健康颗粒物的激活以及有助于疾病结果的非 IgE 激活的新机制。