Neural migratory deficits in congenital heart disease

项目摘要 先天性心脏病（CHD）是最常见的出生缺陷。巨大进步 手术策略和住院治疗显著提高了存活率， CHD婴儿达到成年。CHD幸存者的神经功能预后往往较差， 这给病人和家庭带来了沉重的负担。迫切需要 研究旨在确定与长期相关的大脑成熟改变的原因。 冠心病的神经功能缺损近来已成为临床关注的焦点。皮质减少 生长是CHD患者脑成熟改变的关键标志，但细胞机制 这一过程的根本原因仍不清楚。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 为此，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有了这个模型，我们以前能够确定关键的来源， 新生的皮层神经元和破坏它们的迁移路线。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。 基质在围产期皮质生长。我们建议测试的假设，减少 CHD的脑氧合破坏了神经前体向皮质的迁移， 依赖的方式。了解新生神经元迁移沿着 脆弱和抗性底物是定义分子机制的关键步骤， 微环境线索调节CHD中未成熟皮质的生长。拟议 研究将为基于细胞的再生策略的潜在靶点提供关键见解 以改善日益增长的CHD人群的大脑成熟和神经系统结局。

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.