The Genetic and Biological Determinants of Environmental Airway Disease

环境气道疾病的遗传和生物决定因素

• 批准号: 7734544
• 负责人: David Schwartz
• 金额: $ 85.36万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/7734544
• 关键词: Acute; Allergens; Allogenic; Asthma; Bacterial Toxins; Base Sequence; Biological; Biology; Bronchiolitis; Cells; Chronic; Clinical; Condition; Development; Diet; Disease; Endotoxins; Environmental Exposure; Epigenetic Process; Exposure to; Fibrosis; Genes; Genetic; Genetic Materials; Genetic Polymorphism; Goals; Graft Rejection; House Dust Mite Allergens; Human; Immune; Immune response; Immune system; Immunity; Individual; Infection; Investigation; Lead; Lung; Lung diseases; Mediating; Methylation; Modeling; Mus; Numbers; Obstruction; Outcome; Ovalbumin; Ozone; Particulate Matter; Population; Pregnancy; Process; Pyroglyphidae; Research; Role; Stimulus; Structure of parenchyma of lung; Supplementation; Susceptibility Gene; Techniques; Testing; Thinking; Tissue Sample; Toxic Environmental Substances; Toxin; Transplant Recipients; Transplantation; Vitamins; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; base; cohort; digital; lung allograft; mouse genome; mouse model; novel; programs; pulmonary function

The interplay between innate and adaptive immunity in the lung is central to the development of lung disease including asthma and obliterative bronchiolitis, a condition that occurs with lung transplant rejection. The overall goal of this research program is to identify genes that mediate the host response to a number of environmental toxins and allergens both in mouse models of environmental airway diseases and in human populations. Specific environmental challenges include lipopolysacharide (LPS), allergens (house dust mite and ovalbumin), ozone, and particulate matter. In a human asthma project, our goal is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. We hypothesize that polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. To test this hypothesis, we have identified genes that are differentially expressed by cells in the airway epithelia following specific subsegmental airway challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and will then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. In another line of investigations, we are using mouse models of environmental airway disease to study the effect of pre-exposure to specific environmental toxins and allergens on the host innate immune system to bacterial toxins. The lung is constantly exposed to a broad spectrum of environmental toxins and allergens but the effect that these environmental exposures have on the host innate immune system is not well understood. We have also developed a mouse model of chronic LPS exposure that is characterized by airway inflammation, persistent airway hyper-reactivity, and airway remodeling with thickening of the subepithelial space. The specific cellular interactions that regulate this process and ultimately lead to airways remodeling remain to be elucidated. There is an increasing amount of evidence suggesting that other factors besides genetics contributes to the development of asthma. For instance, diet and vitamin supplementation, especially during pregnancy, is a potentially important factor. To pursue this, we are examining the role of epigenetics in the development of asthma. We have established a sequence based technique, namely Methylation Specific Digital Karyotaping (MSDK), to identify differentially methylated loci in the mouse genome. Finally, we are examining the interplay between innate and adaptive immunity in the context of transplant biology. Chronic rejection manifest as airway fibrosis limit longterm survival after human lung transplant. Although rejection is thought to occur as a result of the recipient adaptive immune response to the allogenic lung tissue, the lung allograft is also exposed to significant innate immune stimuli in the form of inhalational toxins, infections, and other environmental stimuli. Our hypothesis in this line of investigation is that innate immune activation promotes the development of acute and chronic lung allograft rejection. In order to test this hypothesis we have isolated genetic material and tissue samples from over 200 lung transplant recipients and their respective donors and characterized their clinical outcomes with regards to graft rejection. We have also sought to develop a novel immunologically based murine transplant model of chronic lung rejection to pursue further testing of our hypothesis.

肺部先天性免疫和适应性免疫之间的相互作用是肺部疾病发展的核心，包括哮喘和闭塞性细支气管炎，这是一种伴随肺移植排斥而发生的疾病。 该研究计划的总体目标是在环境气道疾病小鼠模型和人类群体中鉴定介导宿主对多种环境毒素和过敏原反应的基因。 具体的环境挑战包括脂多糖 (LPS)、过敏原（屋尘螨和卵清蛋白）、臭氧和颗粒物。 在人类哮喘项目中，我们的目标是鉴定与哮喘患者气流阻塞和气道炎症发生相关的基因，并确定这些差异表达基因的多态性是否会导致个体易患哮喘。 我们假设哮喘患者在经历特定的亚段气道挑战后气道细胞表达的基因多态性使个体易患哮喘。 为了检验这一假设，我们鉴定了在特定的亚段气道刺激后气道上皮细胞差异表达的基因，这些刺激诱导获得性（屋尘螨）或先天（LPS）免疫反应，然后将确定这些基因的多态性是否与一个单独的、特征明确的家族性哮喘患者队列中的哮喘发展相关。 在另一项研究中，我们正在使用环境气道疾病的小鼠模型来研究预先暴露于特定环境毒素和过敏原对宿主对细菌毒素的先天免疫系统的影响。 肺部不断暴露于多种环境毒素和过敏原，但这些环境暴露对宿主先天免疫系统的影响尚不清楚。 我们还开发了一种慢性 LPS 暴露的小鼠模型，其特征是气道炎症、持续气道高反应性以及伴随上皮下间隙增厚的气道重塑。 调节这一过程并最终导致气道重塑的特定细胞相互作用仍有待阐明。 越来越多的证据表明，除了遗传因素之外，其他因素也会导致哮喘的发生。例如，饮食和维生素补充，尤其是在怀孕期间，是一个潜在的重要因素。 为了实现这一目标，我们正在研究表观遗传学在哮喘发展中的作用。 我们建立了一种基于序列的技术，即甲基化特异性数字核分析（MSDK），以识别小鼠基因组中的差异甲基化位点。 最后，我们正在移植生物学背景下研究先天免疫和适应性免疫之间的相互作用。 慢性排斥表现为气道纤维化，限制了人肺移植后的长期生存。 尽管排斥被认为是由于受体对同种异体肺组织的适应性免疫反应而发生的，但同种异体肺移植物也暴露于吸入毒素、感染和其他环境刺激形式的重要先天免疫刺激。 我们在这一系列研究中的假设是先天免疫激活促进急性和慢性肺同种异体移植排斥的发展。 为了检验这一假设，我们从 200 多名肺移植受者及其各自的供体中分离出遗传物质和组织样本，并描述了他们在移植物排斥方面的临床结果。 我们还试图开发一种新型的基于免疫学的慢性肺排斥反应小鼠移植模型，以进一步检验我们的假设。