Corticospinal Tract Development in Intrauterine Growth Restriction

宫内生长受限时皮质脊髓束的发育

基本信息

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
项目类别：
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&apos ,3&apos -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

2&apos ,3&apos -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

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项目摘要

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.

项目摘要宫内生长限制（IUGR）出生的婴儿有发展大脑的风险麻痹（CP）。但是，尚不确切了解围产期神经系统损伤是如何导致的电动机功能障碍。使用新型的血栓烷A2（TXA2）IUGR的鼠模型，我们以前有在整个大脑中表现出明显的髓磷脂基因（MOBP，PLP1，CNPase，MOG）的显着下调，大脑中皮质脊髓束（CST）体积减少，步态受损。最深刻的伤害发生了当IUGR与产后高氧暴露相结合时，提示“双重命中”机制。这些研究结果支持一个模型，在IUGR之后发生转录变化，以改变少突胶质细胞（OL）使它们更容易受到高氧的影响。我们的发现导致我们提出了与IUGR一起的中心假设产后高氧导致细胞特异性变化对OL转录组的变化，从而导致病理学变化 CST和电机在CP中定义。在AIM 1中，将雇用体内遗传和生化方法该模型以确定IUGR/产后高氧如何改变OL转录组。这个目标将进一步增加理解IUGR后白质（WM）受伤的根本原因。众所周知CST是 AIM 2因痉挛性CP干扰，这是围产期脑损伤中最常见的CP类型，将评估CST 使用先进的体内成像技术开发来证明IUGR/产后高氧如何改变脊髓中下降运动区的发展。在AIM 3中，电动机输入变化，导致远端四肢将使用新型运动测试来量化运动异常和增加的超反射/痉挛。这在此目标中进行的创新电机测试将提供严格量化电动机功能障碍的手段由我们的伤害模型产生的，并将其与CP中的运动功能障碍进行比较。这项研究将通过1）对OL转录组的特定更改的洞察力影响。导致异常髓鞘和CST的发展以及2）扩大对 IUGR中CP表型的开发。这项研究很重要，因为它的定量方法成像方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，为研究人类的新治疗干预提供了基础。最后，这项研究将为应用于独立研究者的应用提供出色的工具。调查将在具有成功心态的既定历史的环境中进行初级教师到独立。在此应用程序的支持下，应用程序将1）提高她的技术技能（Ribotag RNA隔离，下一代测序，鼠MRI，肌电图和运动学测试技术）和2）学习高级生物统计学。未来的独立研究将集中于互动在WM发育中，IUGR/高氧在改变的途径之间以及潜在的治疗干预措施之间可以在鼠模型和最终新生儿患者中直接测试。