Validating MRS lipids as biomarkers of brain injury in neonates with hypoxic-ischemic encephalopathy

摘要

ABSTRACT Jessica L. Wisnowski, PhD is a clinical scientist focused on the development and application of novel neuroimaging biomarkers to aid in the diagnosis of perinatal brain injury and the management of neuroprotective therapies. This mentored career development award will provide her with advanced training and skills in magnetic resonance imaging (MRI), bioinformatics, and cell biology, all of which are essential to ensure her success as an independent investigator leading a clinical translational imaging research laboratory. RESEARCH CONTEXT: Establishing safe and effective neuroprotective therapies for neonatal hypoxic- ischemic encephalopathy (HIE) and other neurological diseases is a priority for the NIH. More than a dozen pharmaceutical agents have shown efficacy for neuroprotection in preclinical trials. To facilitate clinical translation, there is a pressing need for well-validated biomarkers that can accurately document the severity of brain injury, response to neuroprotective therapies, and predict long-term neurodevelopmental outcomes in neonates with HIE. This K23 career development proposal leverages data from the ongoing High-dose Erythropoietin (Epo) for Asphyxia and Encephalopathy (HEAL) trial (NCT02811263) to develop robust, quantitative neuroimaging biomarkers of brain injury for neonatal HIE. The parent HEAL trial, a phase III, randomized-controlled trial, seeks to determine if the combination of Epo + hypothermia (HT) reduces the combined rate of death and neurodevelopmental impairment at 22-26 months over HT alone. Using data from the HEAL Trial, this K23 research project will determine whether lipids, measured non-invasively by MR Spectroscopy (MRS), provide a valid estimate of injury severity and treatment response in neonates with HIE. Under normal physiological conditions, CNS lipids are membrane-bound and highly organized, rendering them virtually undetectable by MRS due to their limited mobility and strong dipolar coupling. However, after hypoxia- ischemia, MRS lipids rise. Prior research has established an association between the rise in MRS lipids and histological indices of brain injury. This project will determine whether MRS lipids are valid predictors of death and neurodevelopmental impairment. As proof of principle that MRS lipids can be used as surrogate endpoints in multisite clinical trials, this study will determine whether Epo therapy decreases the severity of brain injury as evidenced by the MRS lipid biomarkers. CAREER DEVELOPMENT PLAN: Dr. Wisnowski will complete coursework in MR physics, advanced MRS methods, computer programming, bioinformatics and computational methods and then will apply this knowledge and skillset directly to execute her proposed research methods. Dr. Wisnowski’s career development goals will be supported through close mentorship from an interdisciplinary team, attendance at professional meetings and workshops, and participation in seminars and journal clubs, as she works toward securing independent funding.