Asthma and Allergic Disease Center

哮喘及过敏性疾病中心

• 批准号: 7134216
• 负责人: THOMAS A. PLATTS-MILLS
• 金额: $ 96.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134216
• 关键词: allergens; asthma; children; clinical research; inflammation; lung; obesity

DESCRIPTION (provided by applicant): The research program of the University of Virginia has focused on investigating the etiology of asthma, looking both at risk factors for the disease and the complex events surrounding an acute episode. These studies have provided extensive evidence about effects of chronic exposure to indoor allergens, as well as the relevance of viruses to acute episodes in the hospital; the role of chronic sinus disease; and most recently the effects of pH changes in the lung lining fluid. In addition, the studies have addressed the mechanisms by which T cells contribute as effector cells and regulatory cells in allergic disease. The four projects of the current proposal are presented as separate and distinct research plans, but they have developed from, and will continue to involve, strong interactions at multiple levels. Project 1: Allergen exposure, IgE responses, and total IgE in relation to asthma in at risk populations: The studies will investigate: a) the interaction between home exposure, sensitization, and inflammatory responses among adult patients presenting with acute asthma; b) lung symptoms and asthma among teenage children in rural and city schools, focusing on the interaction between physical fitness, obesity, and metabolic syndrome on the one hand, and allergic responses and inflammation on the other. Project 2: CD25+CD4+ T cells and IgE-mediated disease in humans: The phenotype and function of a novel CD25+CD4+ subset associated with IgE responses will be analyzed. Studies will include investigation of the link between these cells and IgE by monitoring circulating T cells in children with atopic dermatitis during the first years of life, and examining the effects of anti-lgE therapy on discrete T cell subsets in asthmatic subjects. Project 3: Impact of chronic hyperplastic eosinophilic sinusitis on asthma: Studies will investigate the hypothesis that the sinus tissue contributes to the systemic inflammatory response through the production of, and recirculation of, TH2-like lymphocytes, eosinophils, basophils, and fibrocytes; and that those cells in turn influence sinus associated lymphatic tissue, bone marrow, and the lungs. Project 4: Mechanisms of pH deviation in asthma and chronic cough: Using new methods of measuring exhaled breath pH, the studies will focus on distinguishing between patients with primary airway acidification and gastric acid aspiration. The studies will address cellular and biochemical pathology related to airway acidification in the setting of chronic cough or acute asthma exacerbations. PROJECT 1: Allergen Exposure, IgE Responses, and Total IgE in Relation to Asthma in at Risk Populations (PI Platts-Mills, T.) PROJECT 1 DESCRIPTION (provided by applicant): Over the last 40 years of the 20th century asthma has become epidemic in most of the Western World. In particular asthma has become an important cause of school absenteeism, hospitalization and mortality among populations living in poverty in the cities of the United States. Although many changes are thought to have contributed to the increase the real reasons for the time course (i.e. 1960-2000) are not clear. However it is clear that the majority of African American children and adults admitted to hospital with asthma are allergic to one or more indoor allergens, particularly those from dust mite or cockroach. Over this same time period there have been major changes in lifestyle leading to decreased time outdoors, more time sedentary and a rise in obesity. To further understand the interaction between different factors contributing to asthma, several different approaches will be employed. The first will use new techniques to measure allergen and endotoxin exposure in homes, and a novel approach to measuring IgE antibodies specific for airborne particles. The objective is to investigate the dose response relationship between exposure and immune responses to allergens for patients living in poverty. The second aim is to assess the relationships between IgE ab response and inflammation among the patients presenting to an emergency department with asthma. These patients are consistently -70% uninsured and 50% from a minority group. In this study the inflammation associated with asthma will be studied using both "traditional" markers such as eosinophilia, exhaled NO (eNO) and sinus CT score; as well as measurements of cytokines in serum and leukotrienes in urine. Finally teenagers aged 14-16 years will be studied to determine the independent effects of physical activity, obesity and allergic sensitization on asthmatic symptoms and airway inflammation. The participants will complete an exercise protocol with lung function and will be assessed for evidence of inflammation and allergic sensitization. The objective is to answer whether obesity, decreased fitness, or the metabolic syndrome influence the symptoms or the physiological effects of asthma. As in specific aim 2, inflammation will be assessed both by traditional markers and by assay of cytokines and leukotrienes. These studies will be applied to both rural and city school age children. The overall objective is to understand the effects of obesity, physical activity and allergic sensitization in relation to symptoms of breathlessness and airway obstruction.

描述（由申请人提供）： 弗吉尼亚大学的研究项目侧重于调查哮喘的病因，研究该疾病的危险因素以及围绕急性发作的复杂事件。这些研究提供了关于长期接触室内过敏原的影响以及病毒与医院急性发作的相关性的广泛证据；慢性鼻窦疾病的作用；以及最近肺内壁液体 pH 值变化的影响。此外，这些研究还探讨了 T 细胞作为效应细胞和调节细胞在过敏性疾病中发挥作用的机制。当前提案的四个项目作为单独且不同的研究计划提出，但它们是从多个层面的强有力的相互作用中发展起来的，并将继续涉及多个层面的强有力的相互作用。项目 1：高危人群中与哮喘相关的过敏原暴露、IgE 反应和总 IgE：研究将调查： a) 患有急性哮喘的成年患者的家庭暴露、致敏和炎症反应之间的相互作用； b) 农村和城市学校青少年儿童的肺部症状和哮喘，一方面关注身体健康、肥胖和代谢综合征之间的相互作用，另一方面关注过敏反应和炎症之间的相互作用。项目 2：人类 CD25+CD4+ T 细胞和 IgE 介导的疾病：将分析与 IgE 反应相关的新型 CD25+CD4+ 亚群的表型和功能。研究将包括通过监测患有特应性皮炎的儿童在出生后最初几年的循环T细胞来调查这些细胞与IgE之间的联系，并检查抗IgE治疗对哮喘受试者离散T细胞亚群的影响。项目3：慢性增生性嗜酸性粒细胞性鼻窦炎对哮喘的影响：研究将调查鼻窦组织通过TH2样淋巴细胞、嗜酸性粒细胞、嗜碱性粒细胞和纤维细胞的产生和再循环促进全身炎症反应的假设；这些细胞反过来影响鼻窦相关的淋巴组织、骨髓和肺部。项目4：哮喘和慢性咳嗽中pH值偏差的机制：利用测量呼出气pH值的新方法，研究重点是区分初级气道酸化患者和胃酸误吸患者。这些研究将解决慢性咳嗽或哮喘急性发作时与气道酸化相关的细胞和生化病理学问题。 项目 1：高危人群中与哮喘相关的过敏原暴露、IgE 反应和总 IgE（PI Platts-Mills，T.） 项目 1 描述（由申请人提供）： 20 世纪最后 40 年，哮喘在西方世界大部分地区流行。特别是，哮喘已成为美国城市贫困人口缺课、住院和死亡的重要原因。尽管许多变化被认为促成了这一增长，但时间进程（即 1960-2000 年）的真正原因尚不清楚。然而，很明显，大多数因哮喘入院的非裔美国儿童和成人对一种或多种室内过敏原过敏，特别是尘螨或蟑螂。同一时期，生活方式发生了重大变化，导致户外时间减少、久坐时间增加以及肥胖率上升。为了进一步了解导致哮喘的不同因素之间的相互作用，将采用几种不同的方法。第一个将使用新技术来测量家庭中的过敏原和内毒素暴露，以及一种测量空气颗粒特异性 IgE 抗体的新方法。目的是调查贫困患者的过敏原暴露与免疫反应之间的剂量反应关系。第二个目的是评估急诊室哮喘患者中 IgE 抗体反应与炎症之间的关系。这些患者中 -70% 始终没有保险，其中 50% 来自少数群体。在这项研究中，将使用“传统”标志物（例如嗜酸性粒细胞增多、呼出一氧化氮（eNO）和鼻窦 CT 评分）来研究与哮喘相关的炎症。以及血清中细胞因子和尿液中白三烯的测量。最后，将对 14-16 岁的青少年进行研究，以确定体力活动、肥胖和过敏对哮喘症状和气道炎症的独立影响。参与者将完成一项肺功能锻炼方案，并将评估炎症和过敏性过敏的证据。目的是回答肥胖、体质下降或代谢综合征是否会影响哮喘的症状或生理效应。与具体目标 2 一样，将通过传统标记物以及细胞因子和白三烯测定来评估炎症。这些研究将适用于农村和城市学龄儿童。总体目标是了解肥胖、体力活动和过敏对呼吸困难和气道阻塞症状的影响。