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

描述(申请人提供)：囊性纤维化是高加索人群中最常见的致命性遗传病。囊性纤维化跨膜电导调节器(CFTR)的突变会影响其作为氯离子通道的能力。最近的转基因猪CF模型的发展表明，新生儿的CF肺在出生时没有细菌和炎症，会被一种混合的微生物群定植，这可能会在临床上出现肺功能明显恶化之前启动早期的炎症变化。由于慢性感染和炎症在CF疾病的进展和恶化中起核心作用，许多临床医生和研究人员将重点放在识别与CF感染和炎症相关的病原体上。然而，最近的研究表明，非病原体，如所有人在多个粘膜部位携带的共生菌群，不断地激活宿主的先天和获得性免疫系统。“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反应的适当发展和功能。我们推测，患有CF的新生儿获得共生菌群可能在启动致病性炎症反应中发挥关键作用，从而导致肺损伤。获得性共生菌群最初可能与非CF婴儿相同，但可能会因CFTR突变对粘膜环境的直接或间接影响而改变。这种改变的菌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，可能存在一个新的治疗机会来调节这种共生菌群，或者以一种方式操纵其免疫调节功能，以中断以CF为特征的潜伏的炎症和损伤循环。我们建议在三个具体目标上验证我们的假设：(1)描述CF婴儿和非CF对照组肠道和呼吸道微生物群的获得和演变；(2)确定这两个队列中微生物区系和炎症标志物之间的关系；以及(3)确定早期肺功能下降是否与炎症生物标志物或微生物组组成/功能有关。这项研究是新颖的，因为它关注的是一个很少研究的人群，而此时干预措施可能会显著影响这种致命疾病的进展并保护肺功能。它的创新之处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，从而增加了这项研究的结果转化为临床实践的可能性。(摘要结束)

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)