Mitochondrial Dysfunction and White Matter Injury

总结 白色物质损伤（White matter injury，白质损伤）是小儿脑性瘫痪（cerebral palsy，CP）最常见的原因。最近， 脑梗死的病理模式已从坏死性脑损伤转变为孤立或弥漫性髓鞘形成 与少突胶质细胞（OLs）的成熟缺陷相关的失败。虽然OL机制和其他 OLs成熟失败的机制是： 很神秘我们假设，成熟失败的OL发生继发于他们的线粒体 功能障碍，以提供足够的能量供应用于OL分化。这种生物能量学危机并不致命 并由多次短暂的低氧血症-复氧引起，该事件在 早产儿为了验证这一假设，我们提供了一种新的WM髓鞘形成失败的小鼠模型， 在早产儿中观察到的生理变化（全身氧合、心率和呼吸率） 间歇性缺氧事件在新生小鼠中密切再现。这个模型再现了感觉运动 在人类中与EAE表型一致的缺陷。目标1将确定在这个模型中，OL成熟 失败是髓鞘形成缺陷的主要细胞机制。目标2确定了 线粒体功能障碍以支持OL成熟和脑髓鞘形成。我们建议，在 缺氧发作时线粒体膜瞬时透化。这会暂时阻止ATP 质子动力随着线粒体膜的透化而丧失。鉴于 早产儿经历50 - 200（！）产后数周内每天发生短暂的低氧血症， 生物能量学缺陷支持充分的WM发展代表了可想象的机制假说。 目的3确定是否抑制线粒体膜的瞬时透化， 间歇性低氧可减轻脑缺血的严重程度。使用亲环素D KO小鼠，我们将确定致病性 线粒体透化在OLs成熟的生物能量学危机中的作用。如果这个主要假设 如果这一提议得到证实，那么线粒体不能支持正常发育将被称为新的 机制，为。这确定了预防/治疗糖尿病的新的治疗目标：（1）限制 缺氧事件中线粒体膜透化。

SUMMARY White matter injury (WMI) is the most common cause of cerebral palsy (CP) in children. Recently, a pathological pattern of WMI have shifted from necrotic brain damage to isolated or diffuse myelination failure associated with maturational defect of olygodendrocytes (OLs). While mechanisms for OLs, and other cells degeneration in WMI have been extensively studied, the mechanisms of OLs maturational failure are cryptic. We hypothesized, that maturational failure of OLs occurs secondary to their mitochondrial dysfunction to provide adequate energy supply for OLs differentiation. This bioenergetics crisis is not lethal and caused by multiple, brief episodes of hypoxemia-reoxygenation, the event very commonly seen in premature infants. To test this hypothesis we offer a novel mouse model of WM myelination failure in which physiological changes (systemic oxygenation, heart and respiratory rates) seen in premature infants during intermittent hypoxic events were closely reproduced in neonatal mice. This model reproduces sensorimotor deficit consistent with WMI phenotype in humans. Aim 1 will determine if in this model, OLs maturational failure is the main cellular mechanism of myelination deficit. Aim 2 determines the mechanism for mitochondrial dysfunction to support OLs maturation and cerebral myelination. We propose, that during hypoxic episodes mitochondrial membrane is transiently permeabilized. This transiently arrests ATP production, as the proton motive force is lost with permeabilization of mitochondrial membrane. Given that premature infants experience 50 - 200 (!) brief hypoxemic events a day, for several postnatal weeks, bioenergetics deficit to support adequate WM development represents conceivable mechanistic hypothesis. Aim 3 determines whether an inhibition of transient permeabilization of mitochondrial membrane during intermittent hypoxia attenuates severity of WMI. Using cyclophilin D KO mice we will determine a pathogenic role for mitochondrial permeabilization in bioenergetics crisis of OLs maturation. If the main hypothesis in this proposal is confirmed, then mitochondrial failure to support proper development will be claimed as the novel mechanism for WMI. This identifies novel therapeutic goals in prevention/treatment of WMI: (1) limit mitochondrial membrane permeabilization during hypoxic event.