Mechanisms of non-IgE Mast Cell Activation by Environmental Particulates

项目摘要 炎症被认为是许多疾病的主要潜在机制， 具有严重病理结果的病因，如自身免疫、癌症、心血管疾病、肺 疾病，神经退行性病变为例。肥大细胞代表了身体先天性感觉系统的一个主要感觉臂， 免疫系统作为环境“传感器”与其他生理和/或生物进行交流 由于它们在粘膜表面、血管附近和周围组织中广泛存在， 神经系统通过R 01 ES 019311的资助，我们已经开始解开非- IgE肥大细胞活化，导致炎症。虽然肥大细胞在一种疾病中被认为是致病性的， 除了过敏症之外的许多疾病的机制知之甚少，关于如何治疗更是知之甚少。 环境毒物触发肥大细胞反应，导致这些疾病的结果。所以我们的 总体研究目标一直集中在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侮辱的第一反应者的作用， 和适应性免疫，以及它们与其他细胞和生理系统的通信。我们的研究 揭示了由颗粒驱动的肥大细胞活化的新的非IgE介导机制（例如， 纳米颗粒、空气污染颗粒物、二氧化硅等），其导致肺部不良结果。 和心血管系统。此外，通过使用杂交小鼠的全基因组关联研究， 多样性小组以及转录组学研究，我们已经发现了非IgE肥大细胞的新的遗传调控， 由微粒驱动的细胞活化特别是，我们已经发现硫氧还蛋白相互作用的调节作用， 蛋白（Txnip）在非IgE肥大细胞活化中的作用。在这个建议中，我们将研究氧化还原独立和 通过环境颗粒（纳米颗粒和周围环境颗粒）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 胞吐作用此外，我们将研究Txnip的作用，使用肥大细胞从患者的慢性炎症。 特发性荨麻疹（一种主要由非IgE机制驱动肥大细胞活化障碍， 由环境暴露引发）。我们的总体目标是描述肥大细胞在 通过更好地了解他们作为环境侮辱第一反应者的作用， 通过微粒和非IgE激活的新机制激活，有助于疾病的结果。

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.