Identifying Potential Therapeutic Targets for Abusive Head Trauma

项目总结 半球低密度的病理生理学机制尚不清楚。这是一种脑损伤的模式，只发生在 幼儿，通常由虐待引起，其中大部分大脑半球位于硬脑膜下 血肿在横跨多个血管区域的计算机断层扫描上显示为低密度。当 硬膜下血肿超过一个半球，损害以单侧为主。最近，我们 成功地诱导出发育类似于人类幼儿的仔猪单侧半球低密度 通过再现这种损伤的临床特征：机械性损伤，中线移位，硬膜下血肿， 癫痫发作、呼吸暂停和换气不足。这种模型会导致年龄相关的神经损伤， 代谢性酸中毒，单侧缺氧缺血型损伤，覆盖大部分大脑皮质。 硬膜下血肿。损伤模式、血管源性水肿的程度和基质的上调 金属蛋白水解酶与年龄有关。大脑半球损害的百分比与 出血面积和发作持续时间。我们的长期目标是了解年龄和受伤的具体情况 开发阻止或抑制头部虐待后组织损伤进展的治疗方法的病理生理学 精神创伤。这项应用的总体目标是确定癫痫发作和出血在 损害的发展和伤害的级联是否可以中止。我们的中心假设是 滥用产生的巨大力量会导致广泛的组织损伤，这主要是由相互作用造成的 局灶性癫痫发作和出血之间的关系，以及由此产生的损害级联可以通过抗癫痫药物来阻止 治疗癫痫的药物。其基本原理是通过了解病理生理学并确定组织是否 可挽救的，然后可能阻止损害的治疗方法可以测试。我们将测试我们的中央 有两个具体目的的假设：1)确定癫痫发作和出血对 出现单侧大脑半球低密度；确定在以下情况下是否可以停止癫痫发作 出现在急诊室的儿童防止了广泛的损害。我们的贡献是第一个 复制潜在协同多因素损伤的大脑半球低密度模型 婴儿和蹒跚学步儿童的相似发育阶段和脑形态 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，因为它脱离了 用单一损伤诱导“重型颅脑损伤”的现状；相反，我们研究了 多起伤害和侮辱的协同相互作用，并使用标准的 儿科重症监护方案与临床相关的结果。拟议的贡献是巨大的 因为针对年龄的治疗可以终止虐待性头部创伤的病理生理学的级联反应 减少神经损伤的严重程度，减少死亡或永久残疾的婴儿数量。

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.