P50 Current Translational/Clinical Research Components

P50 Component 6 Neurocognitive Markers of Fetal Alcohol Spectrum Disorders (Co-PIs: Stephen & P. Kodituwakku; Co-I: E. Kodituwakku) will extend their retrospective studies combining neurobehavioral assessment of adaptive skills, executive control and information processing combined with magnetoencephalographic (MEG) / EEG analyses of pro-saccades and a sustained attention to response task (SART) in FASD, attention deficit hyperactivity disorder (ADHD) and typically developing preadolescents, with the goal of identifying the combination of imaging and behavioral measures that optimally differentiates between these three groups. They now have preliminary data suggesting that MEG measures are more sensitive in differentiating FASD from typically developing controls than behavioral visual prosaccade measures alone. Furthermore, the preliminary data for the SART suggests that different electrophysiological measures differentiate FASD from controls and ADHD children, respectively. Combined with behavioral assessments we expect these measures will help identify a unique signature of prenatal ethanol exposure to facilitate identification of alcohol-related neurodevelopmental disorder (ARND) in pre-adolescent children.

P50 Component 7 Serum MicroRNA Biomarkers of Maternal Alcohol Consumption (Co-PIs: Perrone-Bizzozero & Bakhireva; Co-Is: Savage & Rayburn) is a translational research project examining the effect of maternal drinking during pregnancy on human serum microRNA expression. Preliminary studies have identified at least two miRNAs that are significantly altered in alcohol-consuming pregnant women. Subjects will be recruited and classified according to Dr. Bakhireva’s screening procedure and blood samples collected at term. Serum microRNA will be analyzed using an Affymetrix GeneChip miRNA 3.0 array and the most promising biomarker candidates will be confirmed by rt-PCR. Subsequently, the impact of co-exposure to methadone or nicotine and the effect of ethanol exposure pattern and dose will be systematically evaluated using the mouse model of PAE. The impact of these manipulations on “ethanol-sensitive” microRNAs will be used to help interpret the miRNA data from the clinical study, where ethanol dose and timing and co-exposures may affect the expression profiles of the panel of candidate miRNA biomarkers.

Pilot Project 8I. Systematic profiling and functional assessment of ethanol-induced circular RNAs (PI: Nikolaos Mellios M.D., Ph.D., Assistant Professor, Department of Neurosciences, University of New Mexico School of Medicine; July 2017-June 2019). Circular RNAs (circRNAs) are a novel category of non-coding RNAs that are derived from the back-splicing and covalent joining of exons, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neurodevelopmental disorders such as FASD. Here, the PI is carrying out a systematic profiling of circRNA expression in response to EtOH exposure in human stem cell-derived neuronal cultures and examine the role of EtOH-induced circRNAs on synaptic plasticity and neuronal excitability. Dr. Mellios plans to acquire preliminary data on EtOH-related circRNA profiling and functional validation and apply for extramural grant support, as well as expand our knowledge on circRNA-mediated mechanisms using mouse models of FASD.

Pilot Project 8J. Placental Insufficiency and Prenatal Alcohol Exposure: Investigating the Impact of Multiple Intrauterine Insults on Brain Development (PI: Jessie R. Maxwell, MD, Assistant Professor, Division of Neonatology, Department of Pediatrics, Co-I: Lauren L. Jantzie, PhD, Assistant Professor, Department of Pediatrics & Neurosciences, July 2017-June 2019). Although it is known that PAE and placental insufficiency result in brain injury, the impact on the neurological outcomes from the combined injury is poorly understood. This study fills a gap in knowledge about the connection between placental insufficiency and PAE and the cumulative effects in the developing brain, as there is currently no clinical methods to diagnostically or prognostically stratify infants with PAE and placental insufficiency. The hypothesis is that the combination of PAE+PI significantly worsens brain injury and function compared to either in utero insult alone. Utilizing 7T magnetic resonance imaging, the investigators predict a reduction of major white matter tracts, frontal cortex and hippocampal volumes that will correlate with significantly decreased fractional anisotropy and increased radial diffusivity, axial diffusivity and mean diffusivity in PAE + placental insufficiency offspring compared to controls and either prenatal insult alone. Further, it is predicted that the combination of PAE + placental insufficiency will result in impaired reversal learning and spatial navigation, behaviors sensitive to damage in the frontal cortex and hippocampal formation, respectively. These studies will examine both the microstructural and functional abnormalities during a critical period of neurodevelopment, and could provide vital translational clues to the specific functional brain damage of PAE and placental insufficiency I. Completion of this investigation could facilitate the development of diagnostic clinical biomarkers and novel therapeutic strategies in this underserved pediatric patient population. Dr. Maxwell is currently preparing a K08 grant in which she proposes to continue this line of research. Drs. Jantzie and Savage will serve as mentors on the K08 application.