INTRAUTERINE SMOKE EXPOSURE AND ASTHMA: GENOMIC ORIGINS

描述(由申请人提供)： 据估计，全世界有3亿人患有哮喘，是美国儿童住院的主要原因。发育或胎儿起源假说认为，早期生活事件，特别是发生在子宫内的事件，可以显著影响疾病的易感性。胎肺由结构细胞和免疫细胞组成。胎儿肺的发育是胎儿环境和在特定发育时期表达的基因之间的复杂相互作用。该项目的主要目标是证明对肺发育早期阶段至关重要的结构和免疫基因是以呼吸道阻塞和哮喘为特征的疾病的关键调节因素。此外，我们的目标还是表明，在肺发育早期，其表达被宫内烟雾暴露所改变的基因将在哮喘的发展中发挥显著增加的作用。我们构建了实现这一目标的具体目标如下：(1)通过使用胎肺样本和表达芯片技术来鉴定对肺的正常免疫和结构发育至关重要的基因。这些基因将与哮喘患者的免疫CD4+细胞的表达相关；这些基因中的多态变异也将在建立良好的哮喘队列中测试它们与哮喘的关联。(2)通过对宫内烟雾暴露的胎肺样本进行基因芯片分析，并与未暴露的样本进行比较，筛选出在肺发育早期因宫内烟雾暴露而显著改变表达的基因。这些基因将与在宫内或环境中暴露于或未暴露于烟草烟雾中的CD4+哮喘细胞的表达相关。利用这些基因，将进行侧重于哮喘结果的遗传关联研究以及烟雾暴露对这些结果的修改。(3)通过对宫内烟雾暴露小鼠和非暴露小鼠的实时定量聚合酶链式反应分析，鉴定出的基因将在哮喘小鼠模型中得到验证。然后将详细研究几个基因影响对哮喘易感性至关重要的小鼠免疫细胞T-reg细胞的能力。这些发现可能最终导致确定新的哮喘治疗靶点，以及形成一种用于识别易患哮喘的对象的预后测试。此外，通过将发育基因组学与群体遗传学相结合，这种方法可能可以推广到其他影响肺部或其他器官系统的疾病。公共卫生相关性：该项目寻求确定与正常和宫内烟雾暴露肺发育期间的基因表达特征最密切相关的遗传标记。通过证明这些标记物也与哮喘易感性和结果相关，这些标记物最终可能被用于制定新的治疗和预防策略。由于哮喘仍然是美国儿童住院和缺课的主要原因，新的治疗方法和预防策略都有可能大幅降低与这种疾病相关的发病率和经济负担。(摘要结束)

DESCRIPTION (provided by applicant): Asthma affects an estimated 300 million individuals worldwide and is the leading cause of childhood hospitalizations in the United States. The developmental or fetal origins hypothesis states that early life events, especially those occurring in utero, can markedly affect disease susceptibility. The fetal lung is comprised of both structural and immune cells. The development of the fetal lung is a complex interaction between the fetal environment and genes that are expressed at certain developmental times. The major goal of this project is to demonstrate that the structural and immune genes that are crucial to the early stages of lung development, a time in which airways branching is initiated and completed, are key regulators of a disease characterized by airways obstruction, asthma. Moreover, our goal is also to show that the genes whose expression is modified by in utero smoke exposure during early lung development will play a significantly increased role in the development of asthma. We have structured our specific aims to accomplish this goal as follows: (1) Genes crucial to the normal immune and structural development of the lung will be identified via the use of fetal lung samples and expression microarray technology. These genes will be correlated with the expression of immune CD4+ cells from asthmatics; polymorphic variants in the genes will also be tested for their association with asthma in well-established asthma cohorts. (2) Genes whose expression is significantly altered by in utero smoke exposure during early lung development will be identified by performing microarray analysis on in utero smoke exposed fetal lung samples and comparing to non-exposed samples. These genes will be correlated with the expression CD4+ asthmatic cells that have or have not been exposed to in utero or environmental tobacco smoke. Using these genes, genetic association studies focusing on asthma outcomes and the modification of these outcomes by smoke-exposure will be performed. (3) The genes identified will be validated for their effects in a murine model of asthma by way of real time PCR analysis on in utero smoke exposed and non-exposed mice. Several genes will then be studied in detail for their ability to influence a murine immune cell critical to asthma susceptibility, the T-reg cell. These findings may ultimately lead to identification of new therapeutic targets for asthma, as well as to the formation of a prognostic test for the identification of subjects susceptible to asthma. Additionally, by integrating developmental genomics with population genetics, this approach may be generalizable to other diseases affecting either the lung or other organ systems. PUBLIC HEALTH RELEVANCE: This project seeks to identify genetic markers most closely associated with the genetic expression signature during normal and in utero smoke-exposed lung development. By demonstrating that these markers also correlate with asthma susceptibility and outcomes, the markers may eventually be used to formulate novel therapies and preventative strategies. Since asthma remains the leading cause of childhood hospitalizations and school absences in the United States, both novel therapies and preventative strategies have the potential to substantially decrease the morbidity and financial burden related to this disease. (End of Abstract)