Understanding Mechanisms of Fetal Hypoxic Brain Injury Resulting in Cerebral Pals

描述（由申请人提供）：尽管在过去几十年中围产期实践有所改善，但脑瘫（CP）的发病率（其中大部分为产前起源）基本保持不变。目前还没有直接诊断胎儿脑损伤的方法，我们对导致CP的细胞机制的了解也非常有限。为了研究脑损伤导致脑瘫的机制，我们实验室已经开发了一种临床相关的胎儿缺氧缺血（H-I）兔模型，该模型在新生儿套件中产生运动缺陷。鉴于我们最近的能力，acquisticate胎儿损伤导致产后运动缺陷，在体内神经成像，这项建议调查的细胞和分子机制的损伤导致产后运动缺陷。已经发现在该模型中对H-I的即时脑反应是确定的出生后运动缺陷，因此暗示了损伤的氧化机制的关键作用，在H-I损伤的该阶段占主导地位。自由基被认为是H-I后脑损伤的关键机制，导致后续反应级联的“再灌注损伤”。我们的中心假设是，自由基和抗氧化剂在大脑发育中的相互作用决定了脑损伤的程度。现在可以使用扩散加权成像（DWI）和衍生的表观扩散系数（ADC）非侵入性地评估个体胎儿脑反应，并与出生后结果相关联。该提案调查了由ADC评估并预测出生后结果的即时脑反应是否与伴随的过量自由基产生、线粒体功能障碍以及随后的细胞死亡和凋亡相关。将通过评估两个胎龄兔（早产（79%妊娠）和近足月（90%妊娠））的ADC反应和氧化应激标志物以及对H-I皮质不太敏感和对基底神经节、丘脑和脑干更敏感的脑区，来测试自由基和抗氧化剂的成熟依赖性相互作用的概念。在具体目标1中，我们将确定缺氧缺血后立即通过ADC评估的脑损伤严重程度是否可以预测出生后运动缺陷的程度。在具体目标2中，我们将确定氧化应激和线粒体功能障碍是否是缺氧缺血后脑损伤的原因，如ADC所评估的。第三个特定目标将讨论人胎儿DWI诊断和证实胎儿H-I脑损伤高风险患者的H-I脑损伤和随后的出生后神经功能缺损的可行性和实用性。本项目的长期目标是开发基于DWI的替代标记物，以诊断和治疗人胎脑损伤。公共卫生相关性：本研究旨在利用磁共振成像来提高我们对胎儿脑损伤导致脑瘫和其他运动缺陷的理解。基于动物模型数据，这种理解有可能识别人类胎儿的风险，早期诊断胎儿脑损伤并实施预防或治疗策略，最终减少脑瘫的发生和残疾。

DESCRIPTION (provided by applicant): Despite improvements in perinatal practice during the past several decades, the incidence of cerebral palsy (CP), most of them of antenatal origin, has remained essentially unchanged. Currently there is no way to diagnose human fetal brain injury directly and our understanding of cellular mechanisms causing CP is very limited. To study mechanisms of brain injury resulting in cerebral palsy, a clinically relevant rabbit model of fetal hypoxia-ischemia (H-I) has been developed in our laboratory that produces motor deficits in newborn kits. Given our recent ability to prognosticate fetal injury resulting in postnatal motor deficits using in vivo neuroimaging, this proposal investigates cellular and molecular mechanisms of injury resulting in postnatal motor deficits. Immediate brain response to H-I in this model has been found to be determine postnatal motor deficits thus implying a critical role of oxidative mechanism of injury, predominant at this phase of H-I injury. Free radicals have been implicated as a key mechanism of brain injury after H-I, causing "reperfusion injury" from a cascade of subsequent reactions. Our central hypothesis is that the interaction of free radicals and antioxidants in the developing brain determines the degree of brain injury. The individual fetus brain response can now be assessed non-invasively using diffusion weighted imaging (DWI) and derived apparent diffusion coefficient (ADC) and associated with postnatal outcome. The proposal investigates whether immediate brain response, assessed by the ADC and predictive of postnatal outcome, is associated with concomitant excess free radical production, mitochondrial dysfunction, and consequent cell death and apoptosis. The concept of maturation dependent interaction of free radicals and antioxidants will be tested by assessing ADC response and markers of oxidative stress on two gestational ages of rabbit - preterm (79% gestation) and near term (90% gestation) and in brain regions with less vulnerable to H-I cortex and more vulnerable basal ganglia, thalamus and brainstem. In Specific Aim 1 we will determine whether the severity of brain injury, as assessed by ADC immediately after hypoxia-ischemia, can predict the extent of motor deficits postnatally. In Specific Aim 2 we will determine whether oxidative stress and mitochondrial dysfunction are responsible for brain injury after hypoxia-ischemia as assessed by ADC. The third Specific Aim will address feasibility and utility of the human fetal DWI to diagnose and prognosticate H-I brain injury and ensuing postnatal neurological deficits on patients with high risk of fetal H-I injury. The long term goal of this project is to develop DWI-based surrogate marker to diagnose and treat human fetal brain at the time of injury. PUBLIC HEALTH RELEVANCE: This study is designed to use magnetic resonance imaging to improve our understanding of the fetal brain injury resulting in cerebral palsy and other motor deficits. Based on animal model data, this understanding has the potential to identify human fetuses-at-risk, early diagnose fetal brain injury and implement preventive or therapeutic strategies, ultimately reducing incidents and disabilities of cerebral palsy.