Environmental Proteinases in Human/Experimental Asthma

人类/实验性哮喘中的环境蛋白酶

• 批准号: 7150845
• 负责人: DAVID B CORRY
• 金额: $ 26.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150845
• 关键词: airborne allergen; allergens; asthma; biological signal transduction; children; developmental immunology; disease /disorder etiology; disease /disorder model; dust; endopeptidases; environmental exposure; enzyme activity; fungal proteins; human subject; immunity; inflammation; laboratory mouse; molecular pathology; pathologic process; respiratory hypersensitivity

The broad, long-term objectives of this laboratory are to understand the immunological mechanisms underlying allergic lung disease. This proposal specifically will determine the earliest innate immune signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease. Further, we will determine the relationship between allergenic proteinases in home environments and the development of childhood asthma. Recent studies indicate that allergic asthma is the result of failure of immune tolerogenic mechanisms that are normally activated to suppress inflammatory responses to inhaled antigens. Commonly used experimental allergens such as ovalbumin are only transiently capable of avoiding tolerance and inducing robust airway inflammation and then only if administered initially remotely from the lung followed by airway antigen challenge. In contrast, we have developed more potent allergens derived from sources implicated in human allergic disease. Without requiring special adjuvants or protocols for administration, these fungal and pollen-derived allergens strongly induce allergic lung inflammation by bypassing airway immune tolerogenic mechanisms. These potent allergens contain strong proteinase activities that account entirely for their ability to induce and sustain chronically the asthma phenotype. Although non-fungal proteinases exist and are implicated in human asthma and other allergic disorders, our data indicate that dust from homes of asthmatic children contains primarily fungal proteinases. We therefore propose the novel hypothesis that proteinases represent an essential environmental adjuvant factor that is responsible for inducing allergic disease, especially in early life. The aims of this proposal are therefore to: 1. To evaluate the association between fungal proteinases and childhood asthma; and 2. To functionally characterize a novel innate signaling pathway of the airway activated by proteolytic allergen. We will conduct a case-control study involving Houston-area children with and without asthma to understand the association between active proteinase in house dust and asthma and, further, prepare allergens from fungi isolated from homes of asthmatic children and determine the innate immune mechanism by which they elicit disease in mice. This proposal links human and animal studies to unravel the fundamental immune mechanisms underlying allergic inflammation with the intent to develop novel therapies for asthma.

该实验室的广泛，长期目标是了解免疫机制 潜在的过敏性肺病这项建议将明确确定最早的先天免疫 由过敏原激活的信号传导途径，使肺部适应随后的过敏性肺病。 此外，我们将确定过敏蛋白酶在家庭环境中的关系， 儿童哮喘的发展。最近的研究表明，过敏性哮喘是由于缺乏对 免疫耐受原性机制通常被激活以抑制炎症反应， 吸入抗原。常用的实验过敏原，如卵清蛋白， 避免耐受性和诱导强烈的气道炎症， 远离肺部，然后进行气道抗原激发。相比之下，我们开发了更有效的 来源于涉及人类过敏性疾病的过敏原。无需特殊助剂 或给药方案，这些真菌和花粉来源的过敏原强烈诱导过敏性肺 通过旁路气道免疫耐受机制来预防炎症。这些强有力的过敏原含有强烈的 蛋白酶活性完全解释了它们诱导和慢性维持哮喘的能力， 表型尽管非真菌蛋白酶存在并与人类哮喘和其他过敏性疾病有关， 我们的数据表明，哮喘儿童家中的灰尘主要含有真菌， 蛋白酶 因此，我们提出了新的假设，蛋白酶代表了一个重要的环境佐剂 过敏性疾病是导致过敏性疾病的因素，尤其是在早期生活中。这项建议的目的是 因此，1.探讨真菌蛋白酶与儿童哮喘的关系。到 在功能上表征了蛋白水解过敏原激活的气道的新的先天信号传导途径。 我们将进行一项病例对照研究，包括休斯顿地区有哮喘和无哮喘的儿童， 了解室内灰尘中活性蛋白酶与哮喘之间的关系，并进一步准备 从哮喘儿童家中分离的真菌中提取的过敏原， 它们在小鼠中引发疾病的机制。这项提议将人类和动物研究联系起来， 过敏性炎症的基本免疫机制，旨在开发新的 哮喘的治疗方法