Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

描述（由申请人提供）：在美国，每年约有55,000名早产婴儿在呼吸道和免疫系统正常受到保护并维持在幼稚状态的发育时期出生在“敌对环境”中。RFA-HL-10- 007要求确定疾病机制和生物标志物，以便在早产儿出院时对其随后肺部发病的风险进行分层，因此撰写了本提案。这项临床研究中心（CRC）的提案将研究细胞先天和适应性免疫系统的早产儿依赖性改变，这些改变会导致呼吸道感染和环境刺激物的易感性增加，并导致出生后第一年的呼吸道疾病。先前的研究已经确定了循环和肺淋巴细胞群的发育（成熟）和疾病相关变化，但尚未对其与疾病风险/结果的关系进行全面评估。我们假设，由于早产所呈现的内在和外在因素，细胞和分子免疫成熟度发生了改变，从而降低了对病毒感染的抵抗力，并促进了对肺部的细胞毒性损伤。我们将通过对早产儿、出院时和12个月矫正年龄时采集的外周血淋巴细胞群进行综合表型分析来评估免疫成熟度。淋巴细胞表型将特别在胎龄和能够调节氧化应激的母胎应激源（氧暴露、感染和环境烟草烟雾暴露）的背景下进行分析。此外，我们将通过全基因组表达谱分析评估分离的CDS淋巴细胞分子表型的变化，以发现新的疾病途径并定义与疾病风险相关的基因表达特征。CDS淋巴细胞是一种优先招募到早产儿肺部并能够促进疾病发病的细胞类型。最后，我们建议建立一个统计模型，使用细胞和分子表型以及其他临床变量，对生命第一年肺部发病的风险进行分层。除了CRC单中心提案，我们还提交了一项多中心概念提案，以开发和测试功能性生物ari<er，由呼吸诱导容积描记数据的傅里叶域处理定义，将被测试为1)适用于常规临床实践的可靠肺功能替代品；2)在生命第一年作为肺部发病率的有力预测指标。（摘要结束）

DESCRIPTION (provided by applicant): Approximately 55,000 babies bom prematurely each year in the United States suffer from birth into a "hostile environment" at a time in development when the respiratory tract and Immune system would normally be protected and maintained in a naive state. This proposal is written in response to RFA-HL-10- 007 requesting the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) proposal will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populatons but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particulariy in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CDS lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. Finally, we propose to build a statistical model, using cellular and molecular phenotypes and additonal clinical variables, for stratifying risk of lung morbidity within the first year of life. In addition to the CRC single center proposal, we submit a multicenter concept proposal to develop and test a functional biomari<er, defined by Fourier domain processing of respiratory inductive plethysmography data, that will be tested as 1) a reliable pulmonary function surrogate applicable in routine clinical practice and 2) as a strong predictor of pulmonary morbidity in the first year of life. (End of Abstract) RELEVANCE (See instructions): A highly collaborative team of clinical and laboratory science investigators in Neonatology, Pulmonology and Immunology at the University of Rochester and University at Buffalo are worthing to identify immunologic disease mechanisms and to discover innovative biomarkers to understand and predict the severity of respiratory morbidity in prematurely bom infants. The future of many vulnerable children depends on this pioneering approach to the Prematurity and Respiratory Outcomes Program, PROP.