Perinatal white matter development and fetal hypoxia

描述(由申请人提供)：脑性瘫痪(CP)是新生儿重症监护幸存者神经功能障碍的主要原因。进展的障碍是缺乏合适的CP动物模型和缺乏胎儿脑损伤的诊断工具；这两个问题都在本提案中讨论。我们将利用我们最近建立的模拟急性胎盘功能不全的临床相关的胎儿动物模型，该模型在70%妊娠的胎儿缺氧缺血(H-L)后表现出CP表型。我们先前已经证明，在该模型中，H-L后胎儿脑内产生了活性氧(ROS)和活性氮(RNS)，母亲给予抗氧化剂可以减轻胎儿脑损伤，逆转高张状态。初步研究表明，白质(WM)损伤伴随少突胶质细胞(OL)前体细胞的死亡是由H-L侮辱产生的。我们的方法专注于早产儿脑白质损伤及其后遗症的细胞和分子决定因素，并使用多学科的创新方法，整合了免疫组织化学、流式细胞术、磁共振成像(MRI)电生理学、髓鞘形成和氧化剂生物化学的最新进展。我们的假设是，早产白质对H-L损伤的偏好与OL前体的成熟依赖的脆弱性有关，OL前体的死亡是随后髓鞘形成障碍发生的一个致病因素。我们还将检验这一假设，即OL前体对H-L的易感性与胎儿大脑中活性氧和氮物种的产生有关。其具体目的是确定：(1)胎儿H-L引起的神经行为改变，特别是P1区高张是否与脑白质损伤有关。(2)H-L致OL前体细胞死亡是否与白质纤维束损伤有关。(3)活性氧和氮在早孕期OL前体和脑白质损伤中的作用。我们的目的是了解H-L导致OL前体死亡的因素，并确定OL在体死亡与脑髓鞘损伤的发生之间是否存在因果关系。本项目完成后，我们希望通过了解影响H-L易感性的OL的内在特征，深入了解预防脑白质损伤的策略。白质损伤的更好的临床和生化标志的有效性将得到测试，包括非侵入性的MRI措施和针对胎儿但对母亲实施的安全、无毒的治疗。

DESCRIPTION (provided by applicant): Cerebral palsy (CP) is the leading cause of neurological disability in survivors of neonatal intensive care. The impediments to progress have been a lack of a suitable animal model of CP and a lack of diagnostic tools of fetal brain injury; both are addressed in this proposal. We will utilize a clinically relevant fetal animal mode mimicking acute placental insufficiency recently developed by us, which exhibits a CP phenotype in newborn rabbit pups following fetal hypoxia-ischemia (H-l) at 70% gestation. We have previously shown that reactive oxygen (ROS) and reactive nitrogen species (RNS) are produced in fetal brain after H-l in this model, and administration of antioxidants to the mother ameliorates fetal brain injury and reverses hypertonia. Pilot studies show that white matter (WM) injury accompanied by death of oligodendrocyte (OL) precursors is produced by the H-l insult. Our approach focuses on cellular and molecular determinants of preterm cerebral white matter injury and its sequelae and uses a multidisciplinary innovative approach, integrating recent advances in immunohistochemistry, flow cytometry, magnetic resonance imaging (MRI) electrophysiology, myelination and oxidant biochemistry. Our hypothesis is that the predilection of the preterm white matter to injury from H-l is related to a maturation-dependent vulnerability of OL precursors whose death is a pathogenic factor in the genesis of subsequent myelination disturbances. We will also test the hypothesis that the vulnerability of OL precursors to H-l is related to production of reactive oxygen and nitrogen species in fetal brain. The specific aims are to determine: (1) whether neurobehavioral changes, specifically hypertonia at P1, induced by fetal H-l, are associated with white matter injury. (2) whether death of OL precursors from H-l is associated with subsequent injury to fiber tracts in the white matter. (3) the role of reactive oxygen and nitrogen species in OL precursor and white matter injury at premature gestation. Our objectives are to understand the factors that predispose OL precursors to death from H-l and to establish whether there is a causal relationship between OL death in vivo and the genesis of cerebral myelination disturbances. Upon completion of this project, we hope to gain insight into strategies to prevent white matter injury by understanding intrinsic features of the OL which influence susceptibility to H-l. Efficacy of better clinical and biochemical markers of white matter injury including non-invasive MRI measures and safe, non-toxic therapies aimed at the fetus but administered to the mother will be tested.