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: 9973951
• 负责人: Nobuyuki Ishibashi
• 金额: $ 82.37万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973951
• 关键词: Affinity Chromatography; Anabolism; Axon; Biochemical; Biological Availability; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cells; Child; Chronic; Clinical Research; Clinical Trials; Data; Development; Dose; Drug Kinetics; Event; Family suidae; Fetal Development; Fetal Tissues; Fetus; Genetic; Gestational Age; Human; Hypoxia; Impairment; Individual; Injury; Laboratory Animals; Life; Mediator of activation protein; Messenger RNA; Metabolic; Modeling; Molecular; Morbidity - disease rate; Motor; Mus; Myelin; Neonatal; Neurodevelopmental Deficit; Neurologic; Neurologic Deficit; Nitric Oxide Synthase; Oligodendroglia; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Patients; Peroxonitrite; Pharmaceutical Preparations; Phenylketonurias; Physiological; Placenta; Play; Population; Postoperative Period; Pregnancy; Pregnant Women; Premature Infant; Process; Production; Reaction; Records; Recovery; Regimen; Regulation; Ribosomes; Risk; Role; Safety; Series; Source; Supplementation; Techniques; Testing; Therapeutic; Toxic effect; Translating; Treatment Protocols; Umbilical Cord Blood; biological adaptation to stress; chemical reaction; clinically relevant; congenital heart disorder; design; effective therapy; fetal; fetus hypoxia; imaging biomarker; improved; in utero; in vivo; insight; irradiation; mathematical model; microwave electromagnetic radiation; mouse model; neonatal brain; neurobehavioral test; neuroprotection; novel therapeutics; pharmacokinetic model; prenatal therapy; targeted treatment; tetrahydrobiopterin; tool; translational study; treatment effect; 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.

项目概要/摘要 严重的神经发育迟缓正在成为患者当前最重要的挑战之一 患有先天性心脏病（CHD）。生命早期白质 (WM) 发育异常是造成 在患有先心病的儿童中观察到的神经功能缺损的类型/程度。这些儿童的 WM 出生时尚未成熟 由于子宫内供氧减少。心脏手术后进一步的 WM 损伤通常发生在这些患者中 由于胎儿缺氧而导致 WM 不成熟的同一个体。因此，为了减少 冠心病人群的神经发育缺陷，有必要减轻缺氧引起的 患有 CHD 的胎儿患有 WM 不成熟。然而，目前没有可用的治疗方案。 少突胶质细胞是 WM 中最重要的细胞群。激活一氧化氮合酶 (NOS) 随后产生有毒的过氧亚硝酸盐，是少突胶质细胞毒性中至关重要的分子事件，这是由于 缺氧缺血。一氧化氮合酶 (NOS) 激活后，四氢生物蝶呤 (BH4) 的可用性显着降低，并且 导致 NOS 解偶联并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) 胎儿大脑缺氧减少； iii) 确定 胎儿大脑对缺氧缺血的脆弱性。我们的数据表明，在小鼠中，慢性缺氧 导致大脑 BH4 水平下降。另外缺氧抢救时补充BH4 少突胶质细胞发育不良和髓鞘形成不足，并改善缺氧引起的运动协调缺陷。 这些结果得出我们的主要假设：BH4 水平降低在 引发一系列氧化应激反应，导致胎儿 WM 发育不成熟 冠心病。治疗苯丙酮尿症的大量安全记录证明了 BH4 治疗的可行性 孕妇。接受苯丙酮尿症治疗的儿童 WM 损伤显着改善 早期使用BH4。因此，在大脑发育的最早可行阶段重新利用 BH4 是一种潜在的选择。 治疗方法。总体而言，该提案的目的是建立最佳的保护方案 使用我们独特的仔猪模型（目标 1）和药代动力学研究母体 BH4 对患有 CHD 胎儿的治疗 方法（目标 2）。利用小鼠模型中复杂的遗传工具和生化技术，我们 将阐明我们知之甚少的 BH4 生物利用度和 BH4 在少突胶质细胞中的治疗作用 成熟不良（目标 3）。 拟议的研究将建立一种高度转化的 BH4 治疗方法，旨在减少 CHD 中的 WM 损伤。 通过定义 BH4 诱导的 WM 恢复的机制洞察，我们的建议具有巨大的潜力 为 WM 成熟障碍开发更有针对性和更有效的治疗方案。我们的研究结果将 可能会使 WM 损伤成为发病原因的其他人群受益，例如早产儿。