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

新生儿缺氧/缺血是已知的脑损伤的原因，由血流不足和/或 氧气在出生前、出生期间或出生后向婴儿的大脑输送氧气。医院分娩中发生的情况是 每1000名足月新生儿中约有2-4名，早产儿的发病率急剧上升。氧气的缺乏 输送到大脑会导致广泛的损伤和严重的残疾。血流量的恢复对 然而，抢救缺血组织也会导致严重的脑损伤，部分原因是细胞毒性反应 氧气重新引入时产生的氧物种(ROS)。新生儿的现行标准治疗 缺氧/缺血是在恢复血液后平均4-6小时进行的治疗性低温治疗 流量/氧气输送。一种安全有效的针对再灌注的神经保护干预 复氧早期阶段的损伤将填补婴儿治疗中未得到满足的关键需求 暴露在缺氧/缺血环境中。 我们对线粒体功能的分子研究发现了一种防止体内ROS产生的新方法 早期复氧。事实上，我们的研究第一次：(I)确定了红外光的两个波长 (IRL)通过作用于细胞色素C氧化酶而特异性和可逆地减少线粒体呼吸；以及 (Ii)有文件证明，在复氧时应用的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，一种将治疗性IRL安全地输送到 婴儿的大脑。为了实现这一目标，第一阶段将提出两个实验目标： ·进行体外分子研究，以确定可应用于我们的 大型动物研究(目标1)。 ·在新生儿缺氧/缺血的大型动物模型中建立IRL对HIE的影响(目标2)。我们会 确定IRL对新生猪缺氧/缺血模型神经损伤的影响 研究IRL在未损伤组织中的安全性。 第二阶段将以第一阶段的调查结果为基础，并： ·设计和建造用于测试IRL疗法的iNeuroLUX光传输原型(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的关键安全参数，以推进FDA的批准(目标5)。 该提案结合了多学科的专业知识、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用来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.