Prenatal diagnosis of brain malformations: Improving assessment of prognosis

 描述（由申请人提供）：拟议的研究项目“产前诊断脑畸形：通过基因表达和成像研究改善预后评估”，旨在改善妊娠中期三种常见胎儿脑畸形的产前咨询：脑室扩大（VM），胼胝体异常（ACC）和小脑畸形（CM）。其核心假设是，这些在妊娠中期发现的胎儿脑畸形已经特别改变了大脑解剖结构和胎儿基因转录特征，这些特征是未来神经发育障碍的决定因素。Tarui博士将通过以下具体目的来检验这一假设：（1）使用先进的采集后定量胎儿MRI分析来鉴定每种脑畸形特异性的细微中枢神经系统（CNS）发育畸变;（2）比较脑畸形胎儿与对照胎儿的基因表达谱，以鉴定受影响胎儿的转录异常;和（3）测量18个月时的神经发育结果，并确定目的（1）和（2）中收集的子宫内测量值的预后价值。他将从60个诊断为VM、ACC、CM或正常CNS的中期妊娠胎儿中获取MRI和羊水上清液（sAF）。采用以下方法：（1）采集后定量胎儿MR成像分析（区域体积测量、扩散信号分析、脑表面测量和曲率分析），（2）使用从sAF收集的无细胞RNA的基于人类基因组微阵列的胎儿基因表达谱分析，和（3）Bayley婴儿发育量表III，以评估18个月时所有儿童的神经发育结果，该研究将确定CNS发育紊乱和胎儿转录特征，其将确定每个畸形组特有的出生后神经发育结果。这项研究有可能有助于开发临床有效的产前诊断工具，以提高产前咨询的准确性和一种新的胎儿治疗模型从转录组数据。适用范围可广泛应用于其他胎儿神经系统疾病。这一拟议的5年开发期将用于研究和培训活动，以支持樽井博士在 实现他的长期职业目标，成为一名独立的研究人员，进行临床和转化研究，以改善胎儿神经系统疾病的产前管理。这个职业培训奖将使他能够通过塔夫茨大学的临床和转化研究硕士学位进行正式培训，重点是临床研究设计，先进的生物统计学和基于微阵列的胎儿转录组研究技术。塔夫茨医学中心以其对早期研究人员的生物医学研究和职业发展的坚定承诺而闻名。他的专家指导团队将指导他的职业发展与各种相关的专业知识，由他的主要导师，戴安娜比安奇博士，在胎儿转录组研究的著名专家为代表。

 DESCRIPTION (provided by applicant): 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.