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 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.Public Health Relevance
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