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

基本信息

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
项目类别：
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

项目摘要

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）：围产期缺氧缺血（H-I）脑损伤是儿童获得性残疾的重要危险因素。 H-I 造成的脑损伤是导致脑瘫和肌张力障碍等运动障碍的主要原因。由于潜在生产力的损失以及个人、家庭和社会机构从出生开始直至终生的负担，社会付出的代价是巨大的。相比之下，脑性瘫痪的疾病负担指数高于许多影响晚年的神经退行性疾病。可用于胎儿 H-I 的治疗方法很少。随着临床适用的脑瘫动物模型的出现、研究自由基损伤的创新方法以及新的非侵入性损伤标志物的整合，出现了系统研究胎儿大脑发育至 H-I 的机制的独特机会。四氢生物蝶呤（BH4）是脑功能正常发育的重要辅助因子。 BH4 缺乏也与运动障碍的发展有关。我们之前的研究发现，在动物模型中观察到的运动缺陷取决于大脑不同部位的严重 BH4 缺乏。出生前 H-I 之前用 BH4 治疗胎儿大脑可显着减少出生后观察到的运动缺陷。因此，我们建议运动缺陷的发展可以通过双重打击模型 H-I 与发育低下的 BH4 相结合来解释。我们假设未成熟大脑中的 BH4 通路会被缺氧缺血损伤选择性破坏，从而导致运动缺陷的发生。这一假设将在产前遭受宫内 H-I 损伤的胎兔中进行检验。使用该模型，我们将 (1) 阐明 BH4 浓度是否存在导致严重胎儿脑损伤的阈值； (2)研究神经元中BH4的局部生物合成缺陷是否决定H-I后运动缺陷的发展； (3) 阐明 BH4 治疗是否通过涉及氧化还原的机制起作用。将使用最先进的分析方法来评估 BH4 对大脑反应的影响，以表征 BH4 以及未成熟大脑中 BH4 合成途径的变化。此外，磁共振成像分析将有助于识别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之间的知识差距，并扩大 BH4 疗法在预防和改善儿童运动障碍方面的潜在应用。