Infant NeuroLUX: A Novel Non-invasive Therapeutic Device for Neonatal Hypoxic Brain Injury

新生儿缺氧/缺血是由血流不足和/或缺血性脑损伤引起的已知原因。 氧气输送到婴儿的大脑之前，期间，或出生后。医院分娩的发生率是 每1 000名足月分娩中约有2-4人死亡，早产儿的死亡率急剧上升。氧气不足 输送到大脑导致广泛的损伤和严重的残疾。恢复血流对于 然而，局部缺血组织的抢救也会引起严重的脑损伤，部分原因是由于细胞毒性反应， 再引入氧气时产生的氧物质（ROS）。目前新生儿的标准治疗 缺氧/缺血是在血液恢复后平均4-6小时应用的治疗性低温 流量/氧气输送。一种安全有效的神经保护干预措施，专门针对再灌注 在复氧早期阶段的损伤将填补婴儿治疗中的关键未满足的需求 暴露于缺氧/缺血。 我们对线粒体功能的分子研究揭示了一种新的方法来防止ROS的产生， 早期复氧事实上，我们的研究首次：（i）确定了两种波长的红外光 (IRL)其通过作用于细胞色素c氧化酶特异性且可逆地降低线粒体呼吸;以及 (ii)记录了在复氧时施加的IRL具有神经保护作用并限制ROS的产生。 基于这些数据，我们建议开发iNeuroLUX，这是一种将安全地将治疗性IRL输送到患者的设备。 婴儿大脑为了实现这一目标，第一阶段将提出两个实验目标： ?进行离体分子研究，以确定可应用于我们研究的安全治疗IRL剂量。 大型动物研究（目标1）。 ?在新生儿缺氧/缺血的大动物模型中建立IRL对HIE的影响（目的2）。我们将 确定IRL对缺氧/缺血的新生猪模型中神经损伤的影响， 研究IRL在未受损组织中安全性。 第二阶段将以第一阶段的调查结果为基础，并： ?设计并构建iNeuroLUX光传输原型，用于测试IRL治疗（目标3）。 ?确定iNeuroLUX的疗效，并评估iNeuroLUX联合治疗的概念， 体温过低（目标4）。 ?记录iNeuroLUX的关键安全性参数，以获得FDA批准（目标5）。 该提案结合了多学科专业知识、令人信服的初步数据和最先进的资源 我们的研究团队可以解决一个非常重要的健康问题。

Neonatal hypoxia/ischemia is a known cause of cerebral damage resulting from inadequate blood flow and/or oxygen delivery to the infant brain before, during, or after birth. The occurrence among hospital deliveries is ~2-4 per 1000 full-term births with a drastic increase among premature newborns. The deficit in oxygen delivery to the brain results in extensive damage and severe disabilities. Restoration of blood flow critical for salvage of ischemic tissue, however, also causes significant cerebral damage due in part to cytotoxic reactive oxygen species (ROS) generated upon reintroduction of oxygen. The current standard treatment for neonatal hypoxia/ischemia is therapeutic hypothermia applied on average 4-6 hours after restoration of blood flow/oxygen delivery. A safe and effective neuroprotective intervention that specifically targets reperfusion injury during the early phase of reoxygenation would fill a critical unmet need in the treatment of infants exposed to hypoxia/ischemia. Our molecular studies on mitochondrial function uncovered a novel method to prevent ROS generation during early reoxygenation. Indeed, our studies have, for the first time: (i) identified two wavelengths of infrared light (IRL) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase; and (ii) documented that IRL, applied at the time of reoxygenation, is neuroprotective and limits ROS generation. Based on these data, we propose develop iNeuroLUX, a device that will safely deliver therapeutic IRL to the infant brain. To achieve this goal, Phase I will propose 2 experimental aims: ? Conduct ex vivo molecular investigation to define the safe therapeutic IRL dose that can be applied in our large animal studies (Aim 1). ? Establish the effect of IRL on HIE in a large animal model of neonatal hypoxia/ischemia (Aim 2). We will determine the effects of IRL on neurologic damage in a neonate swine model of hypoxia/ischemia and investigate safety of IRL in undamaged tissues. Phase II will build upon the findings in the first phase and: ? Design and construct a iNeuroLUX light-delivery prototype for testing IRL therapy (Aim 3). ? Establish the efficacy of iNeuroLUX and evaluate the concept of iNeuroLUX combination therapy with hypothermia (Aim 4). ? Document critical safety parameters of iNeuroLUX to move forward with FDA approval (Aim 5). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our research team to address a highly significant health problem.