HOST DETERMINANTS OF ORGANIC DUST INDUCED AIRWAY DISEASE

有机粉尘诱发气道疾病的宿主决定因素

• 批准号: 6343653
• 负责人: David A Schwartz
• 金额: $ 25.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-10 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6343653
• 关键词: clinical research; dosage; dust; endotoxins; family genetics; gender difference; gene expression; genetic mapping; genetic susceptibility; grain; human subject; inflammation; laboratory mouse; lipopolysaccharides; pneumoconiosis; pollution related respiratory disorder; respiratory airflow disorder

The goals of this proposal are to determine whether the airway response to inhaled endotoxin is a genetically based trait in humans and to assess to what extent the expression of this trait is influenced by gender. Occupational and environmental exposure to grain dust can cause asthma and bronchitis. Endotoxin appears to be one of the primary components of grain dust (and other organic dusts) that causes airway inflammation and airflow obstruction. Lipopolysaccharide (LPS) is a specific type of endotoxin found in the cell wall of gram-negative bacteria. In a murine model, we have confirmed that LPS resistance is determined by a single gene (Lps response gene), and we have localized this gene to a 220,000 base pair region on chromosome 4. In preliminary human studies, we have shown that most health, non-asthmatic, non-apoptotic, life-timer non-cigarette smoking volunteers develop airflow obstruction with challenged with increasing concentrations of inhaled LPS. However, approximately 10% of subjects developed marked airflow obstruction after inhaling trivial amounts of LPS and 15% of subjects appear to be hyporesponsive after inhaling over 40 micrograms of LPS. In addition, females demonstrate greater bronchial sensitivity to inhaled LPS than males. These results lead us to hypothesize that the airway response to inhaled LPS is a genetically determined complex trait in humans. Moreover, gender appears to substantially influence the airway response to inhaled LPS. We will use a familial cohort design to determine whether the airway response to inhaled endotoxin is a genetically based trait in humans, and to assess to what extent the expression of this trait is influence by gender. The study design is dependent on two interactive stages. In the first stage, we will screen a relatively large population of healthy, unrelated volunteers (n=200) with incremental doses of inhaled LPS. This will allow us to identify approximately 50 study subjects who will serve as "sensitive" or "hyporesponsive" probands. These sensitive and hyporesponsive probands will be used to identify families for the second stage of this investigation. In the second stage of the study, we will evaluate the airway response to incremental doses of inhaled LPS among 100 first degree relatives of up to 50 sensitive and hyporesponsive probands. Finds from this study will help us to determine why only a small portion of workers develop airway disease when exposed to organic dust.

本提案的目标是确定气道对 吸入的内毒素是人类的一种遗传特征， 这种特质的表达在多大程度上受到性别的影响。 谷物粉尘的职业和环境暴露可引起哮喘， 支气管炎内毒素似乎是谷物的主要成分之一 粉尘（和其他有机粉尘），导致气道炎症和气流 梗阻脂多糖（LPS）是一种特殊类型的内毒素 存在于革兰氏阴性菌的细胞壁中。在小鼠模型中，我们 已经证实LPS抗性是由单个基因（LPS）决定的， 反应基因），我们已经将该基因定位到220，000个碱基对 4号染色体上的区域。在初步的人类研究中，我们已经表明， 最健康、无哮喘、无细胞凋亡、终生不吸烟 吸烟志愿者发展气流阻塞， 增加吸入LPS的浓度。然而，大约10%的 受试者在吸入少量 大量的LPS和15%的受试者出现低反应后， 吸入了超过40微克的脂多糖此外，女性表现出 支气管对吸入LPS的敏感性高于男性。这些结果 使我们假设气道对吸入性脂多糖的反应是一种 由基因决定的复杂特征此外，性别似乎 从而显著影响气道对吸入LPS的反应。我们将使用 一个家族性队列设计，以确定是否气道反应， 吸入的内毒素是人类的一种遗传特征， 性别对这一特征的表达有多大的影响。研究 设计取决于两个交互阶段。在第一阶段，我们将 筛选一个相对较大的健康、无关的志愿者群体 （n=200）增加吸入LPS剂量。这将使我们能够 确定大约50名研究受试者，他们将作为“敏感”或 “反应迟钝”先证者这些敏感和低反应的先证者 将用于确定家庭的第二阶段， 调查在研究的第二阶段，我们会评估 100个一级患者对递增剂量吸入LPS的气道反应 多达50个敏感和低反应先证者的亲属。调查结果来自 这项研究将帮助我们确定为什么只有一小部分工人 暴露在有机粉尘中会导致呼吸道疾病。