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: 10557837
• 负责人: Nobuyuki Ishibashi
• 金额: $ 79.55万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557837
• 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; Mediating; Mediator; 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; Risk Reduction; Role; Safety; Series; Source; Structure; 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; porcine 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.

项目摘要/摘要 显着的神经发育延迟正在成为患者当前最重要的挑战之一 先天性心脏病（CHD）。生命早期的异常白质（WM）开发 CHD儿童观察到的神经缺陷的类型/程度。在这些孩子中，Wm出生时不成熟 由于子宫内的氧气供应减少。心脏手术后的进一步WM损伤通常发生 由于胎儿缺氧而导致WM不成熟的人。因此，为了减少 冠心病种群中的神经发育缺陷，有必要减轻缺氧引起的 WM在胎儿中不成熟。但是目前尚无治疗选择。 少突胶质细胞是WM中最突出的细胞群。一氧化氮合酶（NOS）的激活 其次是产生有毒的过氧亚硝酸盐是由于少突胶质细胞毒性的关键分子事件 缺氧 - 异常。激活NOS和 导致毒性过氧亚硝酸盐的NOS解偶联和产生，从而导致氧化应激。重要的是BH4 水平：i）在正常胎儿发育期间增加； ii）减少缺氧胎儿大脑；和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 导致脑BH4水平的耗竭。另外，在缺氧救援期间补充BH4 少突胶质细胞的肿瘤急性和低切髓并改善缺氧引起的运动配位缺陷。 这些结果导致了我们的主要假设，即降低的BH4水平在 触发一系列未成熟WM发育的氧化应激反应， 冠心。苯酮尿症治疗中的广泛安全记录表明，BH4治疗可行性 孕妇。在接受苯酮尿治疗的儿童中发现了WM损伤的明显改善 早期BH4。因此，在最早可行的大脑发育阶段使用重新利用BH4是一种潜力 治疗方法。总体而言，该提案的目的旨在建立最佳的保护方案 使用我们独特的仔猪模型（AIM 1）和药代动力学用CHD用CHD治疗胎儿的母体BH4治疗 方法（目标2）。利用小鼠模型中的复杂遗传工具和生化技术，我们 将阐明BH4在少突胶质细胞中BH4的BH4生物利用度和治疗作用不足 不饱和（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恢复潜在的机械洞察力，我们的建议具有巨大的潜力 为WM不饱和而开发更多有针对性和有效的治疗选择。我们研究的结果将 WM受伤是发病率的来源的其他人群，例如早产儿。