The proposed research project Prenatal diagnosis of brain malformations: improving assessment of prognosis through gene expression and imaging studies, aims to improve prenatal counseling with regard to three commonly detected fetal brain malformations in the second trimester: cerebral ventriculomegaly (VM), abnormalities of the corpus callosum (ACC), and cerebellar malformations (CM). Its central hypothesis is that these fetal brain malformations identified in the second trimester of pregnancy have specifically altered brain anatomy and fetal gene transcription signatures that are determinant of future neurodevelopmental impairments. Dr. Tarui will test this hypothesis with the following Specific Aims: (1) To use advanced post- acquisition quantitative fetal MRI analyses to identify subtle central nervous system (CNS) developmental aberrations that are specific to each brain malformation; (2) To compare gene expression profiles from fetuses with brain malformations with those of control fetuses, in order to identify transcriptional abnormalities in affected fetuss; and (3) To measure neurodevelopmental outcomes at 18 months, and determine the prognostic value of in utero measures collected in Aims (1) and (2). He will acquire MRI and amniotic fluid supernatant (sAF) from 60 second trimester fetuses with a diagnosis of VM, ACC, CM, or normal CNS. With approaches of (1) post-acquisition quantitative fetal MR imaging analyses (regional volume measurements, diffusion signal analyses, cerebral surface measurement, and curvature analyses), (2) human genome microarray based fetal gene expression profiles analyses using cell free RNA collected from sAF, and (3) the Bayley Scales of Infant Development III to assess all children's neurodevelopmental outcomes at 18 months, the study will determine disturbed CNS development and fetal transcription signature that will determine postnatal neurodevelopmental outcome, specific to each malformation group. This research has the potential to contribute to the development of clinically valid prenatal diagnostic tools to improve accuracy of prenatal counseling and a novel fetal therapy model from transcriptomic data. Application can be broad to other fetal neurological disorders. This proposed 5-year development period will be used for research and training activities that will support Dr. Tarui in achieving his long-term career goal of becoming an independent researcher, conducting clinical and translational research to improve the prenatal management of fetal neurological disorders. This career training award would allow him to pursue formal training through a Master's degree in Clinical and Translational Research at Tufts University, with a focus on clinical research design, advanced biostatics, and microarray based fetal transcriptomic research technology. Tufts Medical Center is well known for their strong commitment to the biomedical research and career development of early-stage investigators. His expert mentoring team will guide his career development with varied and relevant expertise represented by his primary mentor, Dr. Diana Bianchi, a renowned expert in fetal transcriptomic research.

Public Health Relevance

In prenatal counseling concerned with fetal brain malformations, prospective parents often receive confusing and conflicting information about long-term neurodevelopmental outcomes for the child, because of the technical limitations in current fetal neuroimaging and genetic diagnostic tools. This project will implement novel, post-acquisition, quantitative fetal MRI and human genome microarray-based fetal gene expression signature analyses in prenatal counseling concerned with three common fetal brain malformations (cerebral ventriculomegaly, anomalies of corpus callosum, and cerebellar malformations), and assess, at 18 months of age, how this information will predict the neurodevelopmental outcomes for these children. With more accurate anatomical and genetic information, we will have a greater understanding of disease mechanisms and will be able to offer better prognostic counseling.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD079605-05
Application #
9638564
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Parisi, Melissa
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Gaitanis, John; Tarui, Tomo (2018) Nervous System Malformations. Continuum (Minneap Minn) 24:72-95
Tarui, Tomo; Kim, Aimee; Flake, Alan et al. (2017) Amniotic fluid transcriptomics reflects novel disease mechanisms in fetuses with myelomeningocele. Am J Obstet Gynecol 217:587.e1-587.e10