White Matter Protection in the Fetus with Congenital Heart Disease

先天性心脏病胎儿的白质保护

• 批准号: 10414261
• 负责人: Nobuyuki Ishibashi
• 金额: $ 3.75万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414261
• 关键词: Biochemical; Biological Availability; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cardiac; Cardiac Surgery procedures; Cells; Child; Chronic; Data; Development; Drug Kinetics; Event; Fetal Development; Fetus; Genetic; Hypoxia; Impairment; Individual; Life; Molecular; Morbidity - disease rate; Motor; Mus; Neonatal; Neurodevelopmental Deficit; Neurologic; Neurologic Deficit; Nitric Oxide Synthase; Oligodendroglia; Outcome; Oxidative Stress; Oxygen; Patients; Peroxonitrite; Phenylketonurias; Play; Population; Pregnant Women; Premature Infant; Production; Records; Recovery; Regimen; Role; Safety; Series; Source; Supplementation; Techniques; Therapeutic; Toxic effect; biological adaptation to stress; congenital heart disorder; design; effective therapy; fetal; fetus hypoxia; improved; in utero; insight; mouse model; porcine model; targeted treatment; tetrahydrobiopterin; tool; translational study; white matter; white matter injury

PROJECT SUMMARY/ABSTRACT Significant neurodevelopmental delay is emerging as one the most important current challenges for patients with congenital heart disease (CHD). Abnormal white matter (WM) development early in life accounts for the type/degree of neurological deficits observed in children with CHD. In these children, WM is immature at birth due to reduced oxygen supply in utero. Further WM injury after cardiac surgery commonly occurs in these same individuals who have WM immaturity due to fetal hypoxia. Therefore, in order to reduce neurodevelopmental deficits in the CHD population, it will be necessary to mitigate hypoxia-induced WM immaturity in the fetus with CHD. However no treatment options are currently available. Oligodendrocytes are the most prominent cell population in WM. Activation of nitric oxide synthase (NOS) followed by production of the toxic peroxynitrite are crucial molecular events in oligodendrocyte toxicity due to hypoxia-ischemia. Tetrahydrobiopterin (BH4) availability is significantly reduced upon activation of NOS and leads to NOS uncoupling and production of the toxic peroxynitrite, causing oxidative stress. Importantly BH4 levels: i) increase during normal fetal development; ii) decrease in the hypoxic fetal brain; and iii) determine the vulnerability of fetal brain to hypoxia-ischemia. Our data have demonstrated that in mice chronic hypoxia causes a depletion of brain BH4 level. In addition BH4 supplementation during hypoxia rescues oligodendrocyte dysmaturation and hypomyelination and improves hypoxia-induced motor coordination deficits. These results have led to our principal hypothesis that decreased BH4 levels play a critical role in triggering a series of oxidative stress reactions underlying immature WM development in the fetus with CHD. Extensive safety records in the treatment of phenylketonuria demonstrate feasibility of BH4 treatment for pregnant women. Marked improvements in WM injury have been found in children with phenylketonuria treated early with BH4. Thus repurposing BH4 for use at the earliest feasible stage of brain development is a potential therapeutic approach. Overall the aims of this proposal are designed to establish an optimal protective regimen of maternal BH4 treatment for the fetus with CHD using our unique piglet model (Aim 1) and pharmacokinetic approach (Aim 2). Leveraging sophisticated genetic tools and biochemical techniques in the mouse model, we will elucidate poorly understood BH4 bioavailability and therapeutic actions of BH4 in oligodendrocyte dysmaturation (Aim 3). The proposed studies will establish a highly translational BH4 treatment aimed at reducing WM injury in CHD. By defining mechanistic insight underlying BH4-induced WM recovery, our proposal has significant potential to develop more targeted and effective treatment options for WM dysmaturation. The outcome of our studies will likely benefit other populations in whom WM injury is a source of morbidity, such as premature infants.

项目摘要/摘要 严重的神经发育迟缓正在成为患者目前面临的最重要的挑战之一 患有先天性心脏病(CHD)。生命早期白质(WM)发育异常是导致 CHD患儿神经功能缺失的类型/程度。在这些儿童中，WM在出生时就不成熟 由于子宫内氧气供应减少。心脏手术后进一步的WM损伤通常发生在这些 因胎儿缺氧而出现白质未成熟的同一个体。因此，为了减少 CHD人群中的神经发育缺陷，有必要减轻缺氧引起的 先天性心脏病胎儿的WM不成熟。然而，目前还没有可用的治疗方案。 少突胶质细胞是白斑中最突出的细胞群。一氧化氮合酶(NOS)激活 其次是有毒的过氧亚硝酸盐的产生是少突胶质细胞毒性的关键分子事件，这是由于 缺氧-缺血。四氢生物蝶呤(BH4)的利用度在激活NOS和 导致一氧化氮合酶解偶联，产生有毒的过氧亚硝酸盐，引起氧化应激。重要的是BH4 水平：i)在正常胎儿发育期间增加；ii)低氧胎脑减少；以及iii)确定 胎脑对缺氧缺血的易感性。我们的数据表明，在小鼠的慢性缺氧中 导致脑部BH4水平下降。此外，在低氧抢救期间补充BH4 少突胶质细胞发育不成熟和髓鞘减少，并改善缺氧引起的运动协调障碍。 这些结果导致了我们的主要假设，即BH4水平下降在 引发一系列氧化应激反应导致胎儿未成熟的WM发育 先心病。治疗苯丙酮尿症的广泛安全记录表明BH4治疗的可行性 怀孕的女人。在接受苯丙酮尿症治疗的儿童中，发现WM损伤明显改善 早些时候服用了BH4。因此，重新调整BH4的用途，以便在大脑发育的最早可行阶段使用是一种潜在的 治疗方法。总体而言，这项提案的目的是建立最佳保护制度。 使用我们独特的仔猪模型(目标1)对患有先天性心脏病的胎儿进行母体BH4治疗的研究和药代动力学 接近(目标2)。在小鼠模型中利用先进的遗传工具和生化技术，我们 将阐明鲜为人知的BH4生物利用度和BH4在少突胶质细胞中的治疗作用 发育不成熟(目标3)。 拟议的研究将建立一种高度翻译的BH4治疗方法，旨在减少冠心病患者的西医损伤。 通过定义BH4诱导的WM恢复的机制洞察力，我们的建议具有巨大的潜力 为西医发育不成熟制定更有针对性和更有效的治疗方案。我们的研究结果将 可能使WM损伤是发病率来源的其他人群受益，例如早产儿。