Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

描述（由申请人提供）：在美国，每年大约有55，000名早产婴儿在发育过程中出生于“恶劣环境”，此时呼吸道和免疫系统通常会受到保护并维持在幼稚状态。本提案是为了响应RFA-HL-10- 007的要求而编写的，RFA-HL-10- 007要求识别疾病机制和生物标志物，以便在出院时对早产儿进行分层，以确定其后续肺部发病的风险。该临床研究中心（CRC）提案将研究细胞先天和适应性免疫系统中的早产依赖性改变，导致对呼吸道感染和环境刺激物的易感性增加，并导致生命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/结局的关系进行全面评估。我们假设，细胞和分子免疫成熟度改变，由于早产的内在和外在因素，以这种方式，以减少抵抗病毒感染，促进细胞毒性损伤肺。我们将通过对早产时、出院时和校正年龄12个月时采集的外周血中的淋巴细胞群进行综合表型分析来评估免疫成熟度。将特别在胎龄和能够调节氧化应激的母胎应激源（氧气暴露、感染和环境烟草烟雾暴露）的背景下分析淋巴细胞表型。此外，我们将评估分离的CDS淋巴细胞的分子表型的变化，CDS淋巴细胞是一种优先招募到早产儿肺部的细胞类型，能够通过全基因组表达profling促进疾病的发病机制，以揭示新的疾病途径并定义与疾病风险相关的基因表达特征。最后，我们建议建立一个统计模型，使用细胞和分子表型和额外的临床变量，在生命的第一年内肺部发病的风险分层。 除了CRC单中心提案外，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标志物，该功能性生物标志物由呼吸感应体积描记术数据的傅立叶域处理定义，将作为1）适用于常规临床实践的可靠肺功能替代物和2）生命第一年肺部发病率的强预测因子进行测试。(End摘要） 相关性（参见说明）：罗切斯特大学和布法罗大学的新生儿学、肺病学和免疫学的临床和实验室科学研究人员组成的高度合作团队值得确定免疫疾病机制，并发现创新的生物标志物，以了解和预测早产儿呼吸道疾病的严重程度。许多脆弱儿童的未来取决于早产和呼吸结果计划（PROP）的这种开创性方法。

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.