Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

高氧早产儿呼吸系统疾病的功能和淋巴细胞标志物

• 批准号: 8662301
• 负责人: THOMAS J MARIANI
• 金额: $ 53.31万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662301
• 关键词: Age; Biological Markers; Birth; Blood specimen; Buffaloes; CD8B1 gene; Cell surface; Child; Clinical; Clinical Research; Data; Development; Disease; Disease Pathway; Environment; Environmental Irritants; Environmental Tobacco Smoke; Future; Gene Expression; Gene Expression Profile; Genes; Gestational Age; Hospitals; Immune System Diseases; Immune system; Immunologics; Immunology; Individual; Infant; Infection; Infection of amniotic sac and membranes; Instruction; Laboratories; Life; Lung; Lymphocyte; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Neonatal; Neonatology; Outcome; Oxidative Stress; Oxygen; Oxygen Therapy Care; Pathogenesis; Pattern; Phenotype; Plethysmography; Population; Population Distributions; Pre-Eclampsia; Predisposition; Premature Birth; Premature Infant; Pulmonology; Recruitment Activity; Research Personnel; Resistance; Respiratory Process; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Risk; Science; Severities; Statistical Models; Stratification; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Time; Umbilical Cord Blood; United States; Universities; Virus Diseases; Writing; abstracting; cell type; clinical practice; cytotoxic; disorder risk; fetal; genome-wide; in utero; innovation; maternal cigarette smoking; molecular phenotype; novel; peripheral blood; postnatal; premature; programs; pulmonary function; respiratory; response; stressor

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.

描述(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遭受“恶劣环境”的折磨，而此时呼吸道和免疫系统通常会受到保护并保持在幼稚的状态。本建议是应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的肺部发病风险进行分层而编写的。这项临床研究中心(CRC)的提案将调查细胞先天免疫系统和适应性免疫系统的早熟依赖改变，导致对呼吸道感染和环境刺激物的易感性增加，并导致出生第一年的呼吸道发病率。以前的研究已经确定了循环和肺淋巴细胞群体的发育(成熟)和与疾病相关的变化，但尚未对它们与疾病风险/结果的关系进行全面评估。我们假设，细胞和分子的免疫成熟度由于早产的内在和外在因素而改变，从而降低对病毒感染的抵抗力，并促进对肺的细胞毒性损害。我们将通过在早产时、出院时和校正年龄12个月时采集外周血中淋巴细胞群的综合表型来评估免疫成熟度。将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，特别分析淋巴细胞表型。此外，我们将通过全基因组表达检测来评估分离的CDS淋巴细胞的分子表型变化，以发现新的疾病途径并确定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的细胞类型，能够促进疾病的发病机制。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，对出生第一年内肺部发病率的风险进行分层。除了CRC单中心的建议外，我们还提出了一个多中心的概念建议，以开发和测试呼吸感应体积图数据的傅立叶域处理定义的功能生物标志物，该功能生物标志物将被测试为1)适用于常规临床实践的可靠的肺功能替代物，2)作为出生第一年肺部发病率的强烈预测因子。(摘要结束) 相关性(参见说明)：罗切斯特大学和布法罗大学新生儿、肺病学和免疫学方面的临床和实验室科学研究人员高度协作的团队正在努力识别免疫疾病机制，并发现创新的生物标记物，以了解和预测早产儿呼吸道疾病的严重程度。许多弱势儿童的未来取决于这一开创性的早产和呼吸结果方案PROP。