Microbiome acquistion and the progression of inflammation and airway disease in i

描述（由申请人提供）：囊性纤维化是高加索人群中最常见的致死性遗传疾病。囊性纤维化跨膜传导调节因子（CFTR）的突变影响其作为氯离子通道的能力。CF转基因猪模型的最新发展已经证明，出生时没有细菌和炎症的新生CF肺被混合微生物植物群定殖，其可能在临床上明显的肺功能恶化之前引发早期炎性变化。由于慢性感染和炎症在CF疾病进展和恶化中发挥着核心作用，因此许多临床医生和研究人员一直致力于识别与CF感染和炎症相关的病原体。然而，最近在CF领域之外的研究已经清楚地表明，“非病原体”，例如所有人在多个粘膜部位携带的肠道植物群，不断地参与宿主的先天性和适应性免疫系统。“微生物组”和宿主基因组之间的这种相互作用负责保护性炎症和免疫应答的适当发育和功能。我们推测，新生儿CF获得的肺部植物群可能在引发致病性炎症反应，随后导致肺损伤中发挥关键作用。获得性口腔植物群最初可能与非CF婴儿相同，但可能因CFTR突变对粘膜环境的直接或间接影响而改变。这种改变的植物群可能编码不同的代谢和调节功能，并可能直接影响宿主的炎症反应。如果是这样的话，一个新的治疗机会可能存在，以调节这种植物植物群，或操纵其免疫调节功能的方式，中断炎症和损害的特点CF的阴险周期。我们建议在三个具体目标中测试我们的假设：（1）描述CF婴儿和非CF对照组中肠道和呼吸道微生物组的获得和演变;（2）确定这两个队列中微生物组和炎症标志物之间的关系;（3）确定肺功能的早期下降是否与炎症生物标志物或微生物组组成/功能相关。这项研究是新颖的，因为它关注的是一个很少研究的人群，在这个时候，干预措施可能会显着影响这种致命疾病的进展，并保留肺功能。其创新在于将最先进的技术和方法应用于可以简单和非侵入性地收集的样本，从而增加了本研究结果转化为临床实践的可能性。 (End摘要）

DESCRIPTION (provided by applicant): Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations. Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its ability to act as a chloride channel. The recent development of a transgenic pig model of CF has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become colonized with a mixed microbial flora that likely initiates early inflammatory changes which precede clinically apparent deterioration in lung function. Because chronic infection and inflammation play central roles in CF disease progression and exacerbations, many clinicians and researchers have focused on identifying pathogens associated with CF infection and inflammation. Recent studies outside the area of CF, however, have clearly demonstrated that "non- pathogens", such as the commensal flora carried by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems constantly. This interaction between "microbiome" and host genome is responsible for appropriate development and function of protective inflammatory and immune responses. We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical role in initiating pathogenic inflammatory responses that subsequently lead to lung damage. The acquired commensal flora may initially be identical to that of a non-CF infant, but may be altered by the direct or indirect effects of CFTR mutation on the mucosal environment. Such an altered flora is likely to encode different metabolic and regulatory functions, and may directly influence host inflammatory responses. If so, a novel therapeutic opportunity may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions in a way that interrupts the insidious cycle of inflammation and damage that characterizes CF. We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2) Determine the relationship between the microbiota and markers of inflammation in these two cohorts; and (3) Determine whether early declines in lung function are associated with inflammatory biomarkers or microbiome composition/function. This study is novel in its focus on a rarely studied population, at a time when interventions might significantly impact progression of this lethal disease and preserve pulmonary function. Its innovation lies in applying state of the art technologies and methods to samples that can be collected simply and non-invasively, thus increasing the likelihood that the findings of this study can be translated into clinical practice. (End of Abstrct)