Understanding Mechanisms of Fetal Hypoxic Brain Injury Resulting in Cerebral Pals

了解胎儿缺氧性脑损伤导致脑友的机制

基本信息

项目摘要

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.
描述(申请人提供):尽管围产期实践在过去几十年中有所改善,但脑性瘫痪(CP)的发病率基本上保持不变,其中大部分源于产前。目前尚无直接诊断胎儿脑损伤的方法,对脑性瘫痪的细胞机制了解也非常有限。为了研究脑损伤导致脑性瘫痪的机制,我们实验室建立了一种临床相关的兔胎儿缺氧缺血(H-I)模型,该模型造成新生儿运动障碍。鉴于我们最近利用活体神经成像预测胎儿损伤导致出生后运动障碍的能力,本提案研究了损伤导致出生后运动障碍的细胞和分子机制。在该模型中,脑对H-I的即时反应被发现决定了出生后的运动障碍,因此暗示了损伤的氧化机制的关键作用,在H-I损伤的这个阶段占主导地位。自由基被认为是脑缺血后脑损伤的关键机制,可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大脑损伤的程度。现在可以使用扩散加权成像(DWI)和导出的表观扩散系数(ADC)来非侵入性地评估单个胎儿的大脑反应,并与出生后结局相关联。该提案调查了由ADC评估并预测出生后结局的即时大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。通过评估两个胎龄的兔-早产(79%妊娠)和近月(90%妊娠)的ADC反应和氧化应激标志物,以及对H-I皮质不太敏感的脑区和更脆弱的基底节、丘脑和脑干,将检验自由基和抗氧化剂依赖于成熟的相互作用的概念。在具体目标1中,我们将确定脑损伤的严重程度,如在缺氧缺血后立即由ADC评估,是否可以预测出生后运动障碍的程度。在特定的目标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。第三个具体目标是探讨人类胎儿弥散加权成像在诊断和预测新生儿缺氧脑损伤以及胎儿缺氧脑损伤高危患者的后天神经功能缺陷方面的可行性和实用性。该项目的长期目标是开发基于弥散加权成像的替代标记物,用于诊断和治疗损伤时的人胎脑。公共卫生相关性:这项研究旨在利用磁共振成像来提高我们对导致脑瘫和其他运动缺陷的胎儿脑损伤的理解。基于动物模型数据,这种理解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,最终减少脑性瘫痪的事件和残疾。

项目成果

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Alexander Drobyshevsky其他文献

Alexander Drobyshevsky的其他文献

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{{ truncateString('Alexander Drobyshevsky', 18)}}的其他基金

Role of interneurons in resting state fMRI connectivity during normal development and after perinatal brain injury
正常发育期间和围产期脑损伤后中间神经元在静息态 fMRI 连接中的作用
  • 批准号:
    10300698
  • 财政年份:
    2021
  • 资助金额:
    $ 16.68万
  • 项目类别:
Role of interneurons in resting state fMRI connectivity during normal development and after perinatal brain injury
正常发育期间和围产期脑损伤后中间神经元在静息态 fMRI 连接中的作用
  • 批准号:
    10682444
  • 财政年份:
    2021
  • 资助金额:
    $ 16.68万
  • 项目类别:
Role of interneurons in resting state fMRI connectivity during normal development and after perinatal brain injury
正常发育期间和围产期脑损伤后中间神经元在静息态 fMRI 连接中的作用
  • 批准号:
    10461940
  • 财政年份:
    2021
  • 资助金额:
    $ 16.68万
  • 项目类别:
Role of interneurons in resting state fMRI connectivity during normal development and after perinatal brain injury
正常发育期间和围产期脑损伤后中间神经元在静息态 fMRI 连接中的作用
  • 批准号:
    10263546
  • 财政年份:
    2020
  • 资助金额:
    $ 16.68万
  • 项目类别:
Role of gut microbiota in susceptibility of preterm infants to hypoxic brain injury
肠道菌群在早产儿缺氧性脑损伤易感性中的作用
  • 批准号:
    9890188
  • 财政年份:
    2020
  • 资助金额:
    $ 16.68万
  • 项目类别:
Spinal serotonin in cerebral palsy
脑瘫中的脊髓血清素
  • 批准号:
    9511923
  • 财政年份:
    2015
  • 资助金额:
    $ 16.68万
  • 项目类别:
Spinal serotonin in cerebral palsy
脑瘫中的脊髓血清素
  • 批准号:
    9029052
  • 财政年份:
    2015
  • 资助金额:
    $ 16.68万
  • 项目类别:

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