Specialized Pro-Resolving Mediators in Asthma

哮喘专业解决调解员

基本信息

批准号：
10472044
负责人：
Bruce D Levy
金额：
$ 73.58万
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：
2014-05-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472044
关键词：
Acute Address Adverse effects Agonist Allergic Anabolism Anti-Inflammatory Agents Arachidonic Acids Asthma Biological Products Biopsy CD59 Antigen Cell Communication Cell membrane Cells Chronic Chronic Obstructive Pulmonary Disease Dependence Disease Docosahexaenoic Acids Dose Drug Design Enzymes Epithelial Epithelial Cells Essential Fatty Acids Experimental Models Family Fatty Acids Funding Gene Expression Generations Head Health Homeostasis Human Immune In Vitro Inflammation Inflammatory Inflammatory Response Knowledge Laboratories Lead Leukocytes Lipids Lipoxins Lung Measures Mediator of activation protein Modeling Modification Molecular Morbidity - disease rate Mus Pathway interactions Pharmaceutical Preparations Play Process Production Publishing Pulmonary Inflammation Regulation Resolution Respiratory Mucosa Role Severities Signal Transduction Sorting - Cell Movement Stimulus Structure of parenchyma of lung Testing Therapeutic Thinking Tissues Translations Validation Work airway hyperresponsiveness airway inflammation asthma exacerbation asthma model asthmatic asthmatic airway base cell type cellular transduction cysteinyl-leukotriene design eosinophil experimental study granulocyte high dimensionality in vivo insight lipid mediator macrophage molecular imaging mouse model novel pre-clinical prevent programs receptor response spatiotemporal stem translation to humans volunteer

项目摘要

Abstract The proposed experiments will test the hypothesis that specialized pro-resolving mediators (SPMs) and cysteinyl-containing SPMs (CysSPMs) are produced in the lung to counter-regulate pro-phlogistic responses and to promote resolution of lung inflammation, in part via activation of a pro-resolving subset of eosinophils. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness in asthma as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including in eosinophil subsets that are relevant in asthma. With several drugs already developed to block CysLT formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head and identify CysSPMs as natural pro-resolving mediators and novel templates for drug design. To test our hypothesis, we propose three specific aims to:  Determine lung SPM and CysSPM production in acute and chronic allergic lung inflammation,  Establish SPM and CysSPM actions in the resolution of lung inflammatory responses, and  Define roles for lung eosinophil subsets in promoting inflammation resolution. This proposal’s specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.

抽象的拟议的实验将检验以下假设：专门的促解决中介（SPM）和肺部产生含有半胱氨酰的 SPM (CysSPM)，以对抗调节促炎反应并促进肺部炎症的消退，部分是通过激活促消退的嗜酸性粒细胞亚群。尽管我们习惯于看到气道炎症和高反应性的增加哮喘是由于过多的促炎刺激引起的，哮喘的严重程度和持续时间内源性抗炎效应物不足也可能导致病情恶化。人们普遍认为脂质介质在哮喘中发挥促炎作用，但并非所有脂质介质都会引发炎症。现在有几个专门的促解决调解员（SPM）家族已被识别并用于治疗。这些保护性介质以酶促方式衍生自必需脂肪。酸并作为特定受体的激动剂来转导细胞类型特异性功能反应，包括与哮喘相关的嗜酸性粒细胞亚群中，已经开发出几种阻断 CysLT 的药物。形成或作用，选择内源性脂质衍生介质产生以促进的概念解决哮喘气道反应将颠覆传统思维并识别 CysSPM 作为天然的促解决介质和药物设计的新颖模板。为了检验我们的假设，我们提出三个具体目标：  确定急性和慢性过敏性肺部炎症中肺部 SPM 和 CysSPM 的产生，  建立 SPM 和 CysSPM 在解决肺部炎症反应中的作用，以及  定义肺嗜酸性粒细胞亚群在促进炎症消退中的作用。该提案的具体目标是揭示管理解决问题的基本机制健康和疾病中的过敏性气道反应。