Identifying Potential Therapeutic Targets for Abusive Head Trauma

项目摘要 大脑半球低密度的病理生理机制尚不清楚。这是一种脑损伤模式， 幼儿，通常是由于虐待，其中大部分的大脑半球位于硬膜下 血肿在CT上显示为低密度，跨越多个血管区域。当 硬膜下血肿在一个半球，损害主要是单侧的。最近我们 成功诱导发育类似于人类幼儿的小猪单侧半球低密度 通过重建这种损伤的临床特征：机械创伤，中线移位，硬膜下血肿， 癫痫呼吸暂停和换气不足该模型导致年龄依赖性神经功能障碍， 代谢性酸中毒和单侧缺氧缺血性损伤，包括大部分皮层下的 硬膜下血肿损伤模式、血管源性水肿程度和基质表达上调 金属蛋白酶是年龄依赖性的。大脑半球损伤的百分比与 出血面积和发作持续时间。我们的长期目标是了解特定年龄和损伤 病理生理学，以开发停止或抑制虐待头部后组织损伤进展的疗法 外伤本申请的总体目标是确定癫痫发作和出血在 损害的发展以及伤害的连锁反应是否可以中止。我们的中心假设是， 由滥用产生的巨大力量导致广泛的组织损伤， 局灶性癫痫发作和出血之间的联系，由此产生的损害级联反应可以用抗癫痫药物来阻止。 癫痫药基本原理是，通过了解病理生理学并确定组织是否 如果是可以挽救的，那么就可以测试可能阻止损害的治疗方法。我们将测试我们的中央 假设有两个具体目标：1.）确定癫痫发作和出血对 单侧半球低密度发展; 2.）确定是否停止癫痫发作时， 急诊室的儿童可以防止大范围的伤害。我们的贡献是第一 半球低密度模型，复制了潜在的协同多因素损伤级联， 人类婴儿和幼儿的发育阶段和大脑形态， 可以确定癫痫发作的病理生理学和贡献。这种方法是创新的，因为它从 使用单一损伤诱导“严重创伤性脑损伤”的现状;相反，我们研究了 多重损伤和损伤协同相互作用，并使用标准管理30小时重症监护 儿科重症监护协议与临床相关的结果。拟议的贡献是重大的 因为针对特定年龄的治疗方法可以中止虐待性头部创伤的病理生理学级联反应， 降低神经损伤的严重程度，减少婴儿死亡或永久残疾的人数。

PROJECT SUMMARY The pathophysiology of hemispheric hypodensity is unknown. It is a pattern of brain damage only occurring in young children, often resulting from abuse, where the majority of the hemisphere underlying the subdural hematoma appears hypodense on computed tomography spanning multiple vascular territories. When the subdural hematoma is over one hemisphere, the damage is predominantly unilateral. Recently, we successfully induced unilateral hemispheric hypodensity in piglets developmentally similar to human toddlers by re-creating the clinical characteristics of this injury: mechanical trauma, midline shift, subdural hematoma, seizures, apnea, and hypoventilation. This model results in an age-dependent neurologic impairment, metabolic acidosis, and unilateral hypoxic-ischemic-type injury encompassing most of the cortex underlying the subdural hematoma. The pattern of damage, degree of vasogenic edema, and upregulation of matrix metalloproteinases are age-dependent. The percentage of hemispheric damage is positively correlated with hemorrhage area and seizure duration. Our long-term goal is to understand the age- and injury-specific pathophysiology to develop therapies that halt or inhibit the progression of tissue damage after abusive head trauma. The overall objective in this application is to determine the contribution of seizures and hemorrhage in the development of the damage and if the cascades of injury can be aborted. Our central hypothesis is that the large forces generated from abuse causes extensive tissue damage that is primarily driven by an interplay between focal seizures and hemorrhage and that the resultant damage cascades can be arrested with anti- epileptic drugs. The rationale is that by understanding the pathophysiology and determining if the tissue is salvageable, then therapeutics that potentially halt the damage can be tested. We will test our central hypothesis with two specific aims:1.) Determine the contribution of seizures and hemorrhage to the development of unilateral hemispheric hypodensity; and 2.) Determine if stopping seizures at a time when children present to the emergency department prevents the extensive damage. Our contribution is the first model of hemispheric hypodensity that replicates the potentially synergistic multifactorial injury cascades within comparable developmental stages and brain morphology of human infants and toddlers where the pathophysiology and contribution of seizures can be determined. This approach is innovative as it departs from the status quo of using a single injury to induce “severe traumatic brain injury”; instead, we study the synergistic interplay of multiple injuries and insults and manage 30 hours of critical care using standard pediatric critical care protocols with clinically relevant outcomes. The proposed contribution is significant because age-specific therapies that abort the cascades of the pathophysiology of abusive head trauma might reduce the severity of neural damage and reduce the number of infants that die or are permanently disabled.