The candidate for this Career Development Award (CDA) is a pediatric neurosurgeon with a specific interest in advancing the field of post-hemorrhagic hydrocephalus of prematurity (PHH) and improving the care and outcomes of infants with this condition. The rigorous career development program outlined in this proposal has both didactic components and mentored scientific training in the laboratories of Drs. Terrie Inder and David Holtzman at Washington University. The proposed program builds on the strengths of the University's NIH-supported interdisciplinary research centers and the Clinical Research Training Center to focus the candidate's training on clinical research methodologies, cerebrospinal fluid (CSF) protein biology, and neurodevelopment and disability in the preterm infant. The additional training and skills acquired through this CDA will complement the candidate's previous research background and provide new expertise necessary to become an independent clinician-scientist. The central hypotheses of this proposal are that CSF levels of the neurodevelopment proteins L1CAM and amyloid precursor protein (APP) are selectively increased in PHH, and that protracted elevations of these proteins are associated with increased ventricular size, ventriculoperitoneal (VP) shunt requirement, and adverse neurological outcome.
The Specific Aims of this proposal are to: 1) compare the levels of CSF L1CAM and APP in control, PHH, and other neurological conditions; 2) define the association between CSF L1CAM and APP and ventricular size in PHH; and 3) determine the relationship of PHH-associated CSF L1CAM and APP elevations to neurodevelopment outcomes at 18-24 months corrected age. The candidate proposes to leverage his participation in the Hydrocephalus Clinical Research Network to establish a multi- institutional neonatal CSF repository at Washington University. CSF levels of L1CAM and APP in PHH will be measured using ELISAs and compared with those in intraventricular hemorrhage and other neurological conditions common to preterm infants. The association between these CSF proteins and ultrasound-based measures of ventricular size will defined, and the relative gains afforded by CSF L1CAM and APP in identifying infants that require VP shunts will be estimated. Finally, the relationship between CSF L1CAM and APP levels and neurodevelopment outcome will be determined using Bayley Scales of Infant Development-III scoring at 18-24 months corrected age. If successful, these studies will advance the field of PHH by providing crucial data for the development of CSF L1CAM and APP levels as markers of PHH-associated neurological disability. The most immediate benefit of these markers would be to complement existing image-based ventricular measures to better inform clinical trials directed at improving the outcomes of infants with PHH.
Post-hemorrhagic hydrocephalus (PHH) of prematurity is the most frequent cause of severe cognitive and motor disability in preterm infants. Despite its profound effects on neurological outcome, there has been relatively little research into optimizing the treatment of this condition. This project investigates new protein markers intended to provide physicians with important feedback in real time about the effectiveness of treatment in preventing long-term neurological disability.
