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

微生物组的获取以及体内炎症和气道疾病的进展

• 批准号: 8411632
• 负责人: Marie E Egan
• 金额: $ 66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411632
• 关键词: Affect; Area; Bacteria; Biological Markers; Birth; Caucasians; Caucasoid Race; Chloride Channels; Chronic; Clinical; Clinical Management; Computer Simulation; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Detection; Deterioration; Development; Diagnosis; Disease; Disease Progression; Distant; Drug Formulations; Early treatment; Environment; Evolution; Exhalation; Exocrine pancreas; Family suidae; Feces; Gastrointestinal tract structure; Genes; Genome; Hereditary Disease; Human; Immune response; Immune system; Immunity; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Intervention; Lead; Learning; Lung; Lung Inflammation; Lung diseases; Measurable; Measurement; Measures; Metabolic; Methods; Modeling; Molecular; Mucociliary Clearance; Mucous body substance; Mutation; Neonatal Screening; Newborn Infant; Play; Population; Population Study; Probiotics; Process; Research Personnel; Respiratory System; Respiratory physiology; Respiratory tract structure; Ribosomal RNA; Role; Sampling; Severities; Site; Sodium Chloride; Statistical Models; Surface; Techniques; Technology; Testing; Time; Transgenic Organisms; Translating; airway inflammation; children with cystic fibrosis; clinical practice; cohort; commensal microbes; functional decline; in vivo; inflammatory marker; innovation; microbial; microbial colonization; microbial community; microbiome; microorganism; mucosal site; novel; novel therapeutics; pathogen; prebiotics; prevent; programs; pulmonary function; respiratory; treatment strategy

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)

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命遗传疾病。囊性纤维化跨膜电导调节剂（CFTR）的突变会影响其充当氯化物通道的能力。 CF的转基因猪模型的最新发展表明，没有细菌和出生时没有细菌和炎症的新生CF被混合的微生物菌群殖民，可能会引发早期炎症性变化，这在肺功能上临床上明显恶化。由于慢性感染和炎症在CF疾病进展和恶化中起着核心作用，因此许多临床医生和研究人员致力于识别与CF感染和炎症相关的病原体。然而，CF领域以外的最新研究清楚地表明，“非病原体”，例如所有人类在多个粘膜部位携带的共生菌群，使宿主的先天和适应性免疫系统不断吸引。 “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。我们假设新生儿与CF一起获得共生菌群可能在发起致病性炎症反应中起关键作用，这随后导致肺部损伤。获得的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。这种改变的植物可能会编码不同的代谢和调节功能，并可能直接影响宿主炎症反应。如果是这样，可能会有一种新型的治疗机会来调节这种共同的菌群，或者以中断阴险的炎症和损害循环的方式操纵其免疫调节功能。我们建议在三个特定目的中检验我们的假设：（1）描述CF婴儿和非CF对照中肠道和呼吸道微生物组的获取和演变； （2）确定这两个队列中菌群与炎症标记之间的关系； （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/功能有关。这项研究是新颖的，重点是很少研究的人群，在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的情况下。它的创新在于将艺术技术和方法应用于可以简单和非侵入性收集的样品，从而增加了这项研究的发现可以转化为临床实践的可能性。 （Abstrct的结尾）