Neural migratory deficits in congenital heart disease

先天性心脏病的神经迁移缺陷

• 批准号: 10162877
• 负责人: Paul David Morton
• 金额: $ 13.86万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162877
• 关键词: Adult; Animals; Area; Autopsy; Blood Vessels; Brain; Caring; Cell Therapy; Cells; Cerebral Hypoxia; Chronic; Clinical; Complex; Congenital Abnormality; Congenital Heart Defects; Cues; Data; Destinations; Development; Environment; Etiology; Family; Family suidae; Future; Goals; Growth; Hospitals; Human; Hypoxia; Impairment; Infant; Investigation; Label; Lead; Life; Modeling; Molecular; Neonatal; Neurologic Deficit; Neurological outcome; Neurons; Newborn Infant; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Perinatal; Population; Pre-Clinical Model; Process; Reporting; Research; Resistance; Route; Source; Surface; Survival Rate; Survivors; Testing; Veterinary Medicine; base; brain tissue; cerebral oxygenation; college; congenital heart disorder; experience; frontal lobe; fundamental research; improved; in vivo; insight; migration; neonate; nerve stem cell; neuroblast; newborn neuron; novel; peer; perinatal development; pre-clinical; regenerative; relating to nervous system; spatiotemporal; subventricular zone; white matter

Project Summary Congenital heart disease (CHD) is the most common birth defect. Tremendous advances in surgical strategies and hospital care markedly increased survival rates such that a majority of CHD infants reach adulthood. CHD survivors often suffer poor neurological outcomes compared with their peers, which pose substantial burdens on patients and families. The urgent need for research aimed at identifying the cause(s) of altered brain maturation associated with long-term neurological deficits in CHD has recently been brought into clinical focus. Reduced cortical growth is a key signature of altered brain maturation in CHD but the cellular mechanisms underlying this process remain unknown. The primary goal of our proposal is to determine how CHD alters neuronal migration to the cortex during critical stages of brain development. To accomplish this, we will utilize a newly developed preclinical swine model of CHD as a platform for cell-dynamic studies. With this model, we were previously able to identify key sources of newborn cortical neurons and disruption to one of their migratory routes. Our novel preliminary data reveal numerous complex migratory paths of newborn neurons along a diverse host of substrates during perinatal cortical growth. We propose to test the hypothesis that reduced cerebral oxygenation in CHD disrupts neural precursor migration to the cortex in a substrate- dependent manner. Understanding the relationship between newborn neuronal migration along vulnerable and resistant substrates is a critical step in defining the molecular mechanisms and micro-environmental cues regulating immature cortical growth in CHD. The proposed investigation will provide key insights into potential targets for cell-based regenerative strategies to improve brain maturation and neurological outcomes in the growing CHD population.

项目概要 先天性心脏病（CHD）是最常见的出生缺陷。取得了巨大进步 手术策略和医院护理显着提高了生存率，使得大多数患者 CHD 婴儿成年后。与其他冠心病幸存者相比，冠心病幸存者的神经系统结果往往较差 与同龄人的交往，给患者和家庭带来沉重负担。迫切需要 旨在确定与长期相关的大脑成熟改变的原因的研究 CHD 的神经功能缺损最近已成为临床关注的焦点。皮质减少 生长是先心病患者大脑成熟改变的一个关键特征，但细胞机制 这一过程的背后仍然未知。我们提案的主要目标是确定如何 CHD 在大脑发育的关键阶段改变神经元向皮质的迁移。到 为了实现这一目标，我们将利用新开发的 CHD 临床前猪模型作为平台 用于细胞动力学研究。通过这个模型，我们之前能够识别关键来源 新生皮质神经元及其迁移路线之一的破坏。我们的小说初稿 数据揭示了新生神经元沿着不同宿主的许多复杂的迁移路径 围产期皮质生长期间的基质。我们建议检验减少的假设 CHD 中的脑氧合破坏了基底中神经前体向皮质的迁移 依赖方式。了解新生儿神经元迁移之间的关系 脆弱和耐药的底物是定义分子机制和 微环境线索调节先心病中不成熟的皮质生长。拟议的 研究将为基于细胞的再生策略的潜在目标提供重要见解 改善不断增长的先心病人群的大脑成熟和神经系统结果。

项目成果

Neuroblast migration along cellular substrates in the developing porcine brain.

• DOI: 10.1016/j.stemcr.2022.07.015
• 发表时间: 2022-09-13
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Porter, Demisha D. L.;Henry, Sara N.;Ahmed, Sadia;Rizzo, Amy L.;Makhlouf, Rita;Gregg, Collin;Morton, Paul D.
• 通讯作者: Morton, Paul D.