Corticospinal Tract Development in Intrauterine Growth Restriction

宫内生长受限时皮质脊髓束的发育

• 批准号: 10591594
• 负责人: Jill Chang
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591594
• 关键词: 2' ,3' -Cyclic-Nucleotide Phosphodiesterases; 3-Dimensional; Acceleration; Adult; Affect; Anatomy; Biochemical; Bioinformatics; Biomedical Engineering; Biometry; Birth Weight; Brain; Brain Injuries; Brain Stem; Brain region; Cardiopulmonary; Cell Death; Cells; Cerebral Palsy; Cerebrum; Corticospinal Tracts; Demyelinations; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Distal; Down-Regulation; Dyskinetic syndrome; Electromyography; Environment; Exposure to; Extensor; Faculty; Fetal Growth; Fetal Growth Retardation; Fiber; Flexor; Foundations; Future; Gait; Genes; Genetic; Genetic Transcription; Gestational Age; Human; Hyperoxia; Hyperreflexia; Image; Imaging Techniques; Impairment; Infant; Injury; Investigation; Joints; Knowledge; Learning; Lesion; Limb structure; Locomotion; Magnetic Resonance Imaging; Manuscripts; Mentors; Mentorship; Messenger RNA; Methods; Modeling; Modification; Morbidity - disease rate; Motor; Movement; Mus; Muscle; Myelin; Nervous System Trauma; Neurologic; Oligodendroglia; Ontology; Pathologic; Pathway interactions; Perinatal; Perinatal Brain Injury; Phenotype; Physical therapy; Positioning Attribute; Predisposition; Pregnancy; Preparation; RNA; Recording of previous events; Research; Research Personnel; RiboTag; Ribosomes; Risk; Spasm; Spastic Cerebral Palsy; Spinal Cord; Technical Expertise; Techniques; Testing; Therapeutic Intervention; Thromboxane A2; Time; Transcript; differential expression; imaging modality; in vivo; in vivo imaging; innovation; insight; kinematics; limb movement; mortality risk; motor deficit; motor disorder; motor impairment; mouse model; myelination; negative affect; neonatal patient; neonate; neuromuscular; neuromuscular function; next generation sequencing; novel; novel therapeutic intervention; postnatal; response; transcriptome; transcriptomics; white matter; white matter injury

Project Summary Infants born following intrauterine growth restriction (IUGR) are at risk for the development of cerebral palsy (CP). However, it is not precisely understood how perinatal neurologic injury due to IUGR results in motor dysfunction. Using a novel thromboxane A2 (TXA2) murine model of IUGR, we have previously demonstrated significant downregulation of major myelin genes (MoBP, PLP1, CNPase, MOG) in whole brain, decreased corticospinal tract (CST) volume in the brain, and impaired gait. The most profound injury occurred when IUGR was combined with postnatal hyperoxia exposure, suggesting a “double hit” mechanism. These findings support a model in which transcriptional changes occur after IUGR that alter oligodendrocytes (OL) making them more susceptible to hyperoxia. Our findings lead us to the central hypothesis that IUGR with postnatal hyperoxia results in cell specific changes to the OL transcriptome that lead to pathologic changes to the CST and motor deficits seen in CP. In Aim 1, in vivo genetic and biochemical methods will be employed in this model to determine how IUGR/postnatal hyperoxia change the OL transcriptome. This aim will add further understanding to the underlying causes of white matter (WM) injury after IUGR. As CST is known to be disturbed in spastic CP, the most common type of CP in perinatal brain injury, Aim 2 will evaluate CST development using advanced in vivo imaging techniques to demonstrate how IUGR/postnatal hyperoxia alter development of descending motor tracts in the spinal cord. In Aim 3, altered motor input resulting in distal limb movement abnormalities and increased hyperreflexia/ spasms will be quantified using novel motor tests. The innovative motor testing employed in this aim will provide the means to rigorously quantify motor dysfunction resulting from our injury model and compare it to motor dysfunction seen in CP. This study will impact the field by 1) providing insight into specific changes to the OL transcriptome leading to abnormal myelination and CST development and 2) expanding the understanding of the development of the CP phenotype in IUGR. This study is significant because of its quantitative approach to imaging modalities and motor assessments that can be applied more broadly to other murine models of perinatal brain injury and provide a basis for investigating novel therapeutic interventions in humans. Finally, this study will provide an excellent vehicle for the applicant to develop into an independent investigator. Investigations will be performed in an environment with an established history of successful mentorship of junior faculty to independence. With the support of this application, the applicant will 1) advance her technical skills (RiboTag RNA isolation, next generation sequencing, murine MRI, electromyography and kinematic testing techniques) and 2) learn advanced biostatistics. Future independent studies will focus on the interplay between pathways altered by IUGR/hyperoxia in WM development and potential therapeutic interventions that can be directly tested in the murine models and ultimately neonatal patients.

项目摘要 胎儿宫内生长受限（IUGR）后出生的婴儿有脑发育的风险， 麻痹（CP）。然而，由于IUGR引起的围产期神经系统损伤如何导致 运动功能障碍使用一种新的血栓素A2（TXA 2）IUGR小鼠模型，我们以前 证明了全脑主要髓鞘基因（MoBP、PLP 1、CNBP、MOG）的显著下调， 大脑皮质脊髓束（CST）体积减少，步态受损。最严重的伤害发生在 当IUGR与出生后高氧暴露相结合时，提示“双重打击”机制。这些 研究结果支持了一个模型，即IUGR后发生的转录变化改变了少突胶质细胞（OL） 使他们更容易受到高氧的影响。我们的研究结果使我们的核心假设，即IUGR与 出生后高氧导致OL转录组的细胞特异性变化，导致病理变化， 在CP中观察到的CST和运动缺陷。在目标1中，将采用体内遗传和生物化学方法， 该模型用于确定IUGR/出生后高氧如何改变OL转录组。这一目标将进一步增加 了解IUGR后白色物质（WM）损伤的根本原因。众所周知，CST 痉挛性CP是围产期脑损伤中最常见的CP类型，目的2将评估CST 使用先进的体内成像技术来证明IUGR/出生后高氧如何改变 脊髓中下行运动束的发育。在目标3中，运动输入改变导致远端肢体 运动异常和反射亢进/痉挛的增加将使用新的运动测试来量化。的 在这一目标中采用的创新运动测试将提供严格量化运动功能障碍的手段 并将其与CP中观察到的运动功能障碍进行比较。 这项研究将通过以下方式影响该领域：1）深入了解OL转录组的特定变化 导致髓鞘形成和CST发育异常; 2）扩大对 IUGR中CP表型的发展。这项研究是有意义的，因为它的定量方法， 成像模式和运动评估，可以更广泛地应用于其他鼠模型， 围产期脑损伤，并为研究人类新的治疗干预措施提供基础。最后， 这项研究将为申请人发展成为独立调查员提供一个极好的工具。 调查将在一个具有成功指导历史的环境中进行， 初级教师走向独立在本申请的支持下，申请人将1）提高其技术水平， 技能（RiboTag RNA分离，下一代测序，小鼠MRI，肌电图和运动学 测试技术）和2）学习先进的生物统计学。未来的独立研究将集中在相互作用 WM发展中IUGR/高氧改变的途径与潜在的治疗干预之间的关系， 可以直接在小鼠模型和最终的新生儿患者中进行测试。