Tetrahydrobiopterin in Fetal Hypoxic Brain Injury

四氢生物蝶呤在胎儿缺氧性脑损伤中的作用

• 批准号: 8867308
• 负责人: SIDHARTHA TAN
• 金额: $ 39.58万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867308
• 关键词: Affect; Animal Model; Basal Ganglia; Biochemical; Biological Markers; Birth; Blood Circulation; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Part; Brain region; Cell Culture Techniques; Cell Survival; Cells; Cerebral Palsy; Child; Clinical; Congenital Cerebral Palsy; DHFR gene; Development; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Dystonia; Enzymes; Event; Exhibits; Family; Fetus; Free Radicals; Gene Expression; Goals; Health; Hypoxic Brain Damage; Image Analysis; Individual; Injury; Institution; Knowledge; Life; Magnetic Resonance Imaging; Mediating; Methodology; Methods; Mitochondria; Modeling; Motor; Movement Disorders; Muscle Hypertonia; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Newborn Infant; Oryctolagus cuniculus; Oxidation-Reduction; Pathway interactions; Perinatal Hypoxia; Phase; Pregnancy; Prevention; Preventive; Productivity; Research; Risk Factors; Serotonin; Societies; Supplementation; Surrogate Markers; Testing; Thalamic structure; United States Food and Drug Administration; Vitamins; Work; brain cell; brain tissue; burden of illness; cell injury; cofactor; cost; design; disability; effective therapy; enzyme activity; falls; fetal; fetus at risk; high risk; improved; in utero; indexing; injured; innovation; motor deficit; motor disorder; motor impairment; neurobehavioral; postnatal; premature; prenatal; prevent; protein expression; response; sepiapterin; social; tetrahydrobiopterin

DESCRIPTION (provided by applicant): Perinatal hypoxia ischemia (H-I) brain damage is an important risk factor for acquired disabilities in children. Brain damage from H-I is a main cause of motor impairments such as those found in cerebral palsy and dystonia. The costs to society are huge, because of loss of potential productivity and the burden on the individual, family and social institutions, starting at birth and lasting an entire lifetime. Comparatively, CP has a highr index of burden of disease than many neurodegenerative diseases affecting the twilight years of life. There is a paucity of therapies available for fetal H-I. With the availability of a clinicall applicable animal model of cerebral palsy, innovative methods of investigating free radical damage and the integration of new non- invasive markers of injury a unique opportunity arises to systematically investigate the mechanisms of the developing fetal brain to H-I. Tetrahydrobiopterin (BH4) is an important cofactor in normal development of brain function. Deficiency of BH4 is also associated with development of motor disabilities. Our previous research has identified that motor deficits observed in the animal model is dependent on critical BH4 deficiency in different parts of the brain. Treatment of fetal brain with BH4 prior to H-I before birth significantly decreases motor deficits observed after birth. Thus we propose that development of motor deficits can be explained by a double-hit model, H-I in combination with developmentally low BH4. We hypothesize that the BH4 pathway in immature brain is selectively disrupted by hypoxia-ischemia injury leading to development of motor deficits. This hypothesis will be tested in fetal rabbits subjected to in utero H-I injury in the prenatal period. Using this model we will (1) elucidate if there is a threshold for BH4 concentration causing critical fetal brain injury; (2) investigate if the regional biosynthetic deficits of BH4 in neuron determines the development of motor deficits after H-I; (3) elucidate if BH4 treatment acts through a mechanism that involves oxidation- reduction. The influence of BH4 in the brain responses will be assessed by using state-of-the-art analytical methodologies to characterize BH4, and BH4 synthetic pathway changes in the immature brain. Additionally magnetic resonance imaging analysis will help in the identification of at-risk fetuses for neurobehavioral deficits. The successful completion of this work will hopefully bridge the gap in knowledge between the mechanisms of fetal brain injury and in broadening the potential application of BH4 therapies in the prevention and improvement of movement disorders in children.

描述（由申请人提供）：围产期缺血缺血（H-I）脑损伤是儿童获得的残疾的重要危险因素。 H-1的脑损伤是运动障碍的主要原因，例如在脑瘫和肌张力障碍中发现的运动障碍。由于失去潜在的生产力以及个人，家庭和社会机构的负担，从出生开始，持续一生，因此对社会的成本巨大。相比之下，与影响暮光之年的许多神经退行性疾病相比，CP具有疾病负担的高指数。胎儿H-I的疗法很少。随着诊所适用的脑瘫动物模型，研究自由基损害的创新方法和新的非侵入性损伤标志物的整合一个独特的机会，以系统地研究发育中的胎儿脑的机制到H-I。四氢无菌蛋白酶（BH4）是脑功能正常发育的重要辅助因子。 BH4的缺乏也与运动障碍的发展有关。我们先前的研究表明，在动物模型中观察到的运动缺陷取决于大脑不同部位的临界BH4缺乏症。出生前H-I之前用BH4治疗胎儿大脑会显着减少出生后观察到的运动缺陷。因此，我们建议可以通过双重打击模型H-I与发育较低的BH4相结合来解释运动缺陷的发展。我们假设未成熟大脑中的BH4途径被低氧 - 缺血性损伤选择性破坏，从而导致运动缺陷的发展。该假设将在产前期间在子宫内损伤的胎儿兔子中进行检验。 使用此模型，我们将（1）阐明是否存在BH4浓度阈值导致关键的胎儿脑损伤； （2）研究神经元中BH4的区域生物合成缺陷是否决定了H-I后运动缺陷的发展； （3）阐明BH4治疗是否通过涉及还原氧化的机制起作用。 BH4在大脑反应中的影响将通过使用最先进的分析方法来评估BH4的表征，而BH4合成途径的未成熟大脑变化。另外，磁共振成像分析将有助于鉴定神经行为缺陷的高危胎儿。这项工作的成功完成将有望弥合胎儿脑损伤机制与扩大BH4疗法在预防和改善儿童运动障碍中的潜在应用之间的知识之间的差距。