Understanding Mechanisms of Fetal Hypoxic Brain Injury Resulting in Cerebral Pals

描述（由申请人提供）：尽管在过去的几十年里，围产期实践有所改善，但脑瘫（CP）的发病率，其中大多数是产前起源，基本保持不变。目前还没有办法直接诊断人类胎儿脑损伤，我们对引起CP的细胞机制的了解非常有限。为了研究脑损伤导致脑瘫的机制，我们实验室建立了一种具有临床意义的兔胎儿缺氧缺血（H-I）模型，该模型在新生儿中产生运动缺陷。鉴于我们最近使用体内神经成像预测胎儿损伤导致出生后运动缺陷的能力，本建议研究导致出生后运动缺陷的损伤的细胞和分子机制。在这个模型中，大脑对H-I的即时反应被发现决定了出生后的运动缺陷，这意味着氧化损伤机制的关键作用，在H-I损伤的这个阶段占主导地位。自由基被认为是H-I后脑损伤的一个关键机制，通过一系列后续反应引起“再灌注损伤”。我们的中心假设是，发育中的大脑中自由基和抗氧化剂的相互作用决定了脑损伤的程度。个体胎儿脑反应现在可以使用扩散加权成像（DWI）和衍生的表观扩散系数（ADC）进行无创评估，并与产后结局相关。该提案研究了通过ADC评估和预测产后预后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之而来的细胞死亡和凋亡有关。自由基和抗氧化剂的成熟依赖相互作用的概念将通过评估ADC反应和氧化应激标记物在兔的两个胎龄-早产（妊娠79%）和近妊娠（妊娠90%），以及对H-I皮层不那么脆弱的大脑区域，更脆弱的基底节，丘脑和脑干进行测试。在Specific Aim 1中，我们将确定脑损伤的严重程度，如在缺氧缺血后立即通过ADC评估，是否可以预测出生后运动缺陷的程度。在特异性目的2中，我们将确定氧化应激和线粒体功能障碍是否与ADC评估的缺氧缺血后脑损伤有关。第三个具体目标将探讨人类胎儿DWI诊断和预测H-I脑损伤的可行性和实用性，以及胎儿H-I损伤高风险患者随后的出生后神经功能缺陷。本项目的长期目标是开发基于dwi的替代标记物，用于人胎儿脑损伤的诊断和治疗。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认识。基于动物模型数据，这一认识有可能识别人类高危胎儿，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致残。

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.