Infection and inflammation are leading causes of newborn morbidity and mortality. Many sources of infectionincluding blood-stream infections (sepsis) and necrotizing enterocolitis (NEC) are both common and unique tothe neonate as is the systemic response observed in this patient population. NEC is the most common life-threatening gastrointestinal disease among neonates and a leading cause of overall premature infant morbidityand mortality. Further complicating the management of these critically ill infants is the considerable overlap inthe early clinical presentation of NEC and Sepsis. Despite decades of research and clinical practice, theapproach to the neonate under suspicion of sepsis is non-specific and largely supportive. Illustrating this pointis the lack of specific molecular diagnostics for NEC or sepsis. Rather, current practice continues to rely onnon-specific laboratory tests to assist in diagnosing disease and monitoring response to therapy (antibioticsetc.). As a result, the identification of neonates with NEC and more importantly progressive forms of thedisease by current clinical parameters currently occurs at a time when the course of disease is un-alterable.Similarly, the empiric over-use of antibiotics in the neonatal patient population awaiting culture results forpossible sepsis results in potentially significant additional morbidity, including increased incidence of NEC.These observations highlight the increasing biomedical burden imposed by NEC and sepsis and therefore theneed for specific molecular disease classifiers in order to assist in altering their onset and progression. Toaddress this significant unmet need, we have initiated protein biomarker studies in the blood and urine ofneonates that are both diagnostic and prognostic of NEC and sepsis. In this proposal, we intend to verifyand validate an optimized panel of biomarkers that can then be utilized as a disease specific molecular test forneonatal critical care. It is hypothesized that dynamic monitoring of disease specific biomarker panels willadvance our understanding of the clinical pathogenesis of NEC and sepsis in neonates and lead to more timelyand objective patient disease classification and ultimately to improved disease specific treatments. Theproposed research plan has three Specific Aims:1. Verify and validate body fluid candidate protein biomarkers of NEC2. Discover and verify tissue-specific biomarkers, cross-validate to body fluid panels of biomarkers3. Conduct independent prospective validation of optimized biomarker panels on clinical samplesThe PI for this project has assembled a multi-disciplinary team of scientists with complimentary areas ofexpertise in proteomics, bioinformatics, and related technologies in order to pursue this project and its specificaims. Further empowering these studies is our partnership with the NICHD sponsored Neonatal ResearchNetwork (NRN) that will collect the biologic samples and clinical data on infants with a possible diagnosis ofeither NEC or sepsis. The NRN is a NIH sponsored consortium of 22 leading university-based children'shospitals with clinical investigators and research coordinators that together comprise the needed infrastructureand possess the experience necessary to conduct the proposed studies. The Steering Committee that includesa PI from each of the NRN sites has given their approval for these studies thus validating their potentialsignificant impact on neonatal clinical care.
Necrotizing enterocolitis (NEC) is the most common lethal gastrointestinal disease among neonates and surviving infants suffer long-term growth abnormalities, adverse neuro-developmental outcomes and gastrointestinal morbidity including short bowel syndrome. Further complicating the management of these critically ill infants is the considerable overlap in the early clinical presentation of NEC and Sepsis. There is an acute need for disease specific tests that will facilitate rapid decision-making and thus yield improved care and cost effectiveness.
|Sylvester, Karl G; Kastenberg, Zachary J; Moss, R Larry et al. (2017) Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature. J Pediatr 181:80-85.e1|
|Sylvester, Karl G; Ling, Xuefeng B; Liu, G Y et al. (2014) A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants. Gut 63:1284-92|
|Sylvester, Karl G; Ling, Xuefeng B; Liu, Gigi Yuen-Gee et al. (2014) Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants. J Pediatr 164:607-12.e1-7|