The Genetic and Biological Determinants of Environmental

肺部先天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，肺移植排斥反应发生的一种疾病。本研究计划的总体目标是在小鼠环境气道疾病模型和人类群体中确定介导宿主对许多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。

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 long?term 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.