Innate Regulation of Pollen-Oxidase Induced Inflammation

花粉氧化酶引起的炎症的先天调节

• 批准号: 8465467
• 负责人: SANJIV SUR
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8465467
• 关键词: 8-hydroxyguanosine; Address; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Binding; Breathing; Cell Line; Cell Surface Receptors; Cells; Complex; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; Enzymes; Epithelial; Epithelium; Event; Exposure to; Extrinsic asthma; Genetic Materials; Goals; Guanine Nucleotide Exchange Factors; Human; Hypersensitivity; Inflammation; Instruction; Knowledge; Lung Inflammation; Mediating; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mouse Cell Line; Mus; NADPH Oxidase; Nose; OGG1 gene; Oxidases; Oxidative Stress; Pathway interactions; Patients; Pollen; Regulation; Research; Signal Pathway; Signal Transduction; Surface; Symptoms; T-Lymphocyte; TLR4 gene; Testing; Time; Toll-like receptors; airway epithelium; airway inflammation; base; cell type; emergency service responder; human subject; in vivo; inhibitor/antagonist; intraepithelial; novel; novel strategies; prevent; receptor; repaired; respiratory

Exposure to pollens is one of the most common causes of respiratory allergies such as allergic rhinitis and allergic asthma woridwide. We have previously shown that pollens contain an enzyme called NADPH oxidase (pollen-NOX), and that this enzyme is critical for the induction of allergic inflammation. However, very little is known about the molecular mechanism by which these oxidases induce allergic diseases. The goal of this project is to address this critical gap in knowledge about how pollen-NOX induces allergic inflammation. The ain/vay epithelium is the first line of defense against the harmful effects of pollens. Epithelial and intraepithelial dendritic (DCs) cells are two types of cells in the airway epithelium that are the key first responder cells to inhaled pollen allergens. We propose that one of the eariiest events when pollens land on the airway epithelium is that pollen-NOX binds to a receptor on the surface of DCs called Toll-like receptor (TLR4). This cell-surface receptor is best known for its ability to bind to a bacterial product called LPS, but its ability to bind pollen-NOX has not been described. This binding initiates oxidative stress in the DCs that is sufficiently severe to damage DNA, the cells' genetic material. This damaged DNA is repaired by a DNA repair enzyme called OGGI, and 8-oxoG- the damaged base in the DNA, is released. OGGI and 8- oxoG then form a signaling complex in DCs called OGGI-guanine nucleotide exchange factor, or OGG1¿^'^. This induces a signaling cascade that activates DCs and promotes allergic inflammation. This model will be tested in three Specific Aims. In Aim 1 a cell line called 293 and mouse DCs will be used to test how pollen- NOX binds to TLR4, and determine the importance of this binding in the activation of DCs. Aim 2 will test whether DNA damage and repair induced by pollen-NOX is crucial for activating a signaling cascade that induces allergic lung inflammation in mice. Aim 3 will test the human relevance of the observations made in cell lines and mice in Aims 1 and 2. We will determine whether binding of pollen-NOX to TLR4 activates DNA damage/repair-mediated signaling pathways in DCs from healthy human subjects and those with allergic rhinitis. We will also perform nasal challenge with pollen extract to healthy subjects and subjects with allergic rhinitis, and determine if this challenge induces DNA damage and repair in the nose. Achieving these Aims should identify novel molecular pathways utilized by pollen NADPH oxidases to activate DCs and induce allergic inflammation in humans, and so identify novel molecular targets for new treatments of allergic rhinitis and allergic asthma. RELEVANCE (See instructions): Exposure to pollens is one of the most common causes of respiratory allergies woridwide. The objective of this project to elucidate the key molecular signaling pathways that mediate pollen-induced allergic inflammation. This critically important knowledge should allow us ultimately to develop inhibitors of these pathways that could provide a novel approach to preventing pollen exposure-induced symptoms and morbidity in patients with allergic rhinitis and asthma.

接触花粉是引起呼吸道过敏的最常见原因之一，例如过敏性鼻炎和 全球过敏性哮喘。我们之前已经证明花粉含有一种称为 NADPH 的酶 氧化酶（花粉-NOX），这种酶对于诱发过敏性炎症至关重要。然而， 人们对这些氧化酶诱发过敏性疾病的分子机制知之甚少。这 该项目的目标是解决花粉氮氧化物如何诱发过敏的这一关键知识空白 炎。 ain/vay 上皮是抵御花粉有害影响的第一道防线。 上皮细胞和上皮内树突状细胞 (DC) 是气道上皮中的两种细胞类型，它们是 对吸入花粉过敏原的关键第一反应细胞。我们认为花粉发生时最早的事件之一 落在气道上皮上的原因是花粉-NOX 与 DC 表面的一种称为 Toll 样的受体结合 受体（TLR4）。这种细胞表面受体以其与细菌产物结合的能力而闻名。 LPS，但尚未描述其结合花粉-NOX 的能力。这种结合会引发氧化应激 DC 的严重程度足以损害细胞的遗传物质 DNA。这种受损的 DNA 被修复 一种称为 OGGI 的 DNA 修复酶和 8-oxoG（DNA 中受损的碱基）被释放。奥吉和8- 然后，oxoG 在 DC 中形成信号复合物，称为 OGGI-鸟嘌呤核苷酸交换因子，或 OGG1^^'^。 这会诱导信号级联反应，激活树突状细胞并促进过敏性炎症。该模型将是 在三个具体目标中进行了测试。在目标 1 中，将使用名为 293 的细胞系和小鼠 DC 来测试花粉如何 NOX 与 TLR4 结合，并决定这种结合在 DC 激活中的重要性。目标 2 将进行测试 花粉-NOX 诱导的 DNA 损伤和修复是否对于激活信号级联至关重要 引起小鼠过敏性肺部炎症。目标 3 将测试以下观察结果的人类相关性： 目标 1 和 2 中的细胞系和小鼠。我们将确定花粉-NOX 与 TLR4 的结合是否激活 健康人和患有此病的人的 DC 中 DNA 损伤/修复介导的信号通路 过敏性鼻炎。我们还将对健康受试者和患有以下疾病的受试者进行花粉提取物鼻腔挑战 过敏性鼻炎，并确定这种挑战是否会引起鼻子中的 DNA 损伤和修复。实现这些 目标应确定花粉 NADPH 氧化酶利用的新分子途径来激活 DC 和 诱导人类过敏性炎症，从而确定过敏性新疗法的新分子靶点 鼻炎和过敏性哮喘。 相关性（参见说明）： 接触花粉是全球范围内呼吸道过敏的最常见原因之一。的目标 该项目旨在阐明介导花粉诱导过敏的关键分子信号传导途径 炎。这一至关重要的知识将使我们最终能够开发出这些药物的抑制剂 可以提供一种新方法来预防花粉暴露引起的症状的途径 过敏性鼻炎和哮喘患者的发病率。