The effect of congenital renal obstruction on the urinary proteome in infants

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DESCRIPTION (provided by applicant): With the increased use of prenatal screening by ultrasound, more fetuses are being diagnosed as potentially having congenital renal obstruction (2-5% of all pregnancies in the US). To date, the most common cause of renal failure in children is from renal damaged caused by urinary obstruction. Many controversies exist regarding detection, prognosis, and proper management of children with this condition. We hypothesize that congenital renal obstruction results in the release of specific proteins into the urine that reflect changes in protein secretion and shedding from renal tubular cells and other sources. We predict that these changes will vary with onset, duration and severity of the obstruction. In our previous work, we have demonstrated our ability to use state-of-the-art mass spectrometric and proteomic approaches to identify proteins in the urinary proteome in an animal model of postnatal maturation. With this experience, my objective is to identify new markers of obstructive renal damage that could be potential diagnostic or prognostic clinical tools. Our approach will be to use an animal model of neonatal renal obstruction and follow urine composition over time after initiation of the injury. We will study the urinary proteome during obstruction using advanced qualitative and quantitative proteomic methodologies in order to prioritize and identify candidate clinical markers. The discriminatory power of the candidate markers, and their potential for clinical translation, will be determined using directed quantitative proteomics in select human infant cohorts with and without severe renal obstruction. Overall, my long-term career objective is to become an independent pediatric urologic clinician-scientist with a strong commitment to translational research that focuses on biomarker discovery for renal injury. My immediate goals are to acquire a strong background and research experience in mass spectrometry, proteomics, and biomarker validation. During the early portion of my career, I plan to add to my foundation as a clinician investigator through lectures, strong mentorship by Dr. Michael Freeman and others, scientific collaborations, hands-on experience, and didactic coursework that focuses on proteomics, clinical trials, biomarkers, epidemiology, and bioinformatics. My research will be conducted at Children's Hospital Boston in the Urological Diseases Research Center and in the Children's Hospital Boston Proteomics Center. In summary, this project will provide the necessary foundation for a successful career as an independent investigator and will lead to the identification of novel biomarkers that may be used to inform clinical decisions in children affected with congenital renal obstruction.