Identifying potential therapeutic targets for abusive head trauma

确定虐待性头部创伤的潜在治疗目标

• 批准号: 9198842
• 负责人: Beth A Costine-Bartell
• 金额: $ 13.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198842
• 关键词: Acute; Affect; Age; Animal Model; Apnea; Appearance; Atrophic; Autopsy; Awareness; Bilateral; Biomechanics; Blood flow; Brain; Cause of Death; Cell Volumes; Characteristics; Child; Childhood; Childhood Injury; Chlorides; Clinical; Clinical Management; Clinical/Radiologic; Complex; Contralateral; Craniocerebral Trauma; Cytotoxic Cerebral Edema; Data; Detection; Development; Diffuse; Disabled Persons; Distant; Edema; Employee Strikes; Event; Evolution; Exhibits; Extracellular Matrix; Forensic Pathology; Functional disorder; Future; Goals; Gray unit of radiation dose; Guidelines; Hippocampus (Brain); Human; Hypercapnic respiratory failure; Hypoxia; Impairment; Individual; Infant; Injury; International; Ion Transport; Ipsilateral; Ischemia; Knowledge; Lead; Legal patent; Lesion; Life; Light; Magnetic Resonance Imaging; Mechanics; Medical; Mentors; Modeling; Morbidity - disease rate; Motion; Neocortex; Neurons; Neurosciences; Outcome; Oxygen; Pathologic; Pathology; Pattern; Physiological; Physiology; Play; Predisposition; Public Health; Recording of previous events; Regulation; Research Personnel; Role; Seizures; Severities; Shaken baby syndrome; Subclinical Seizures; Subdural Hematoma; Testing; Therapeutic; Time; Tissues; Toddler; Training; Translating; Trauma; Traumatic Brain Injury; Universities; X-Ray Computed Tomography; age difference; age effect; age related; authority; bioimaging; career; disability; effective therapy; experience; gamma-Aminobutyric Acid; in vivo imaging; injured; interest; medical schools; meetings; metabolic rate; mortality; multidisciplinary; nerve injury; neuron loss; postnatal; prevent; public health relevance; response; response to brain injury; successful intervention; symporter; therapeutic target; tool; vascular bed

 DESCRIPTION (provided by applicant): My goal is to become a uniquely qualified, highly productive, independent biomedical investigator of abusive head trauma (AHT) in children. Specifically, I am interested in studying lesion evolution in children and modeling this type of injury in piglets to develop age- and injury-specific treatments that will translate to effective therapies for infants and children. Successful interventions to lessen the burden of morbidity and mortality after injury require understanding the pathophysiological cascades that lead to the extensive injury patterns observed. Currently, the pathophysiology of AHT in children is poorly understood, though clues exist from clinical, radiologic, biomechanical, and pathologic observations. I will initially focus on investigating the age-dependent pathophysiology after injuries and insults characteristic of AHT in our unique immature large- animal model. Though I have considerable basic neuroscience experience and have studied accidental pediatric head trauma in Dr. Duhaime's translational lab, it has only been through recent increasing clinical exposure that I have become aware of this pervasive and understudied public health problem that garners more controversy than data and answers. In order to accurately model AHT in my future independent career, I request additional multidisciplinary training in clinical abusive head trauma through coursework at Harvard Medical School, national and international meetings, a forensic pathology observership, and training by Drs. Duhaime, Newton, and McGuone who are clinicians treating and studying children with AHT. Focused training in what is known about this injury (clinical presentation, injury evolution, and outcome metrics via MRI or autopsy) will allow me to more accurately model, characterize, and interpret this complex injury in our piglets and to translate this to the pathophysiology in children. As one important component, subclinical and clinical seizures are common after AHT and are highly likely to contribute to the pathophysiological cascades due to unique features of the developing brain. In order to study the potential role of seizures in exacerbating damage after AHT, I request training from Dr. Staley who is a world leader in electrographic seizure detection, ion transport, and basic pathophysiology of cytotoxic cerebral edema in the immature brain. I will gain additional in- depth knowledge of developmental differences in the immature brain through coursework at Harvard University. In vivo imaging is a powerful tool to study injured children and observe the parallel injury in our model. Therefore, I seek training through coursework at MIT and the Martinos Center for Bioimaging and with Dr. Hunter who is a world authority in the use of MRI to study head injury in children. With my previous experience in the field of accidental pediatric brain trauma, my team of mentors and collaborators, and the educational opportunities at MGH/ Harvard/ MIT/ The Martinos Center, I believe this training will help me optimize my career goal of shedding light on these mysterious and unfortunately common injuries. Traumatic brain injury is THE leading cause of death and disability in children. In children under the age 2, the majority of severe TBI is due to AHT. Though the injury event is usually occult, there is often evidence of an impact and a subdural hematoma (SDH), the most common intracranial abnormality resulting from inflicted injury. Children with severe injuries typically present with seizures and apneic episodes. Tissue damage is not restricted to the zone immediately underlying the SDH, but patches of damaged parenchyma develop remotely. In severe cases, the injury can evolve into profound damage of the entire hemisphere associated with the subdural hematoma, termed "hemispheric hypodensity" for its appearance on acute computed tomography. Hemispheric delineated damage underlying the SDH with striking sparing of the other hemisphere is an injury pattern unique to immaturity. Infants often exhibit injury in both hemispheres, while toddlers more commonly exhibit relative sparing of the hemisphere contralateral to the SDH. Infants have immature chloride gradients that can result in subclinical seizures that may play a role in exacerbating the extent of tissue damage. No medical treatments currently exist that can halt the progressive evolution of this injury. A significant barrier to understanding the pathophysiology in AHT is a lack of an animal model that replicates these injuries. Here we propose to test the effect of subject age in our unique model of AHT which combines cortical impact, unilateral subdural hematoma, midline shift, apnea, and seizures in order to illuminate the pathophysiology. We have a long history of studying age-dependent differences in response to TBI using piglets developmentally comparable to human infants (PND 7) and toddlers (PND 30). Here we propose to determine the effect of age on 1.) the pattern of tissue injury after AHT injuries determined by MRI and pathology and 2.) the development of seizures after injuries typical of AHT. Our central hypothesis is that combined insults act synergistically to overwhelm the inherent compensatory abilities of the immature brain, leading to more widespread damage in patterns that are age-dependent. Determination of age-dependent patterns in pathology after injury and identification of key components that lead to tissue damage, such as seizures and edema, will produce targets for directed therapies. Therapeutics that abort the cascades set in motion after AHT may reduce the severity of neural injuries and reduce the number of children that die or are permanently disabled from inflicted injuries.

 描述（由申请人提供）：我的目标是成为一个独特的合格，高效，独立的生物医学调查虐待性头部创伤（AHT）的儿童。具体来说，我感兴趣的是研究儿童的病变演变，并在仔猪中模拟这种类型的损伤，以开发针对年龄和损伤的治疗方法，这些治疗方法将转化为针对婴儿和儿童的有效疗法。成功的干预措施，以减轻受伤后的发病率和死亡率的负担，需要了解的病理生理级联反应，导致广泛的损伤模式观察。目前，对儿童AHT的病理生理学了解甚少，尽管从临床、放射学、生物力学和病理学观察中存在线索。我将首先集中研究在我们独特的未成熟大型动物模型中AHT损伤和损伤特征后的年龄依赖性病理生理学。虽然我有相当多的基础神经科学经验，并在Duhaime博士的翻译实验室研究了意外的儿科头部创伤，但直到最近越来越多的临床接触，我才意识到这个普遍存在且未得到充分研究的公共卫生问题，它比数据和答案更具争议性。为了在我未来的独立职业生涯中准确地模拟AHT，我要求在临床虐待头部方面进行额外的多学科培训。 通过哈佛医学院的课程作业、国家和国际会议、法医病理学认证以及Duhaime、Newton和McGuone博士的培训，他们是治疗和研究AHT儿童的临床医生。对这种损伤的已知知识（临床表现、损伤演变和通过MRI或尸检的结局指标）进行重点培训， 我可以更准确地建模、描述和解释小猪的这种复杂损伤，并将其转化为儿童的病理生理学。作为一个重要组成部分，亚临床和临床癫痫发作在AHT后很常见，并且由于发育中大脑的独特特征，极有可能促成病理生理级联反应。为了研究癫痫发作在AHT后加重损伤中的潜在作用，我请求Staley博士的培训，他是电图癫痫发作检测、离子转运和未成熟大脑细胞毒性脑水肿基础病理生理学的世界领导者。我将通过在哈佛大学的课程学习获得关于未成熟大脑发育差异的额外深入知识。活体成像是研究受伤儿童和观察我们模型中平行损伤的有力工具。因此，我通过麻省理工学院和马蒂诺斯生物成像中心的课程以及亨特博士的培训来寻求培训，亨特博士是使用MRI研究儿童头部损伤的世界权威。凭借我以前在意外儿科脑外伤领域的经验，我的导师和合作者团队，以及MGH/哈佛/麻省理工学院/马蒂诺斯中心的教育机会，我相信这次培训将帮助我优化我的职业目标，揭示这些神秘而不幸的常见伤害。 创伤性脑损伤是儿童死亡和残疾的主要原因。在2岁以下的儿童中，大多数 严重TBI的原因是AHT。虽然损伤事件通常是隐匿性的，但通常有撞击和硬膜下血肿（SDH）的证据，这是最常见的颅内异常，由外伤引起。严重受伤的儿童通常会出现癫痫发作和窒息发作。组织损伤并不局限于SDH直接下方的区域，但损伤的软组织补丁远程发展。在严重的情况下，损伤可演变为与硬膜下血肿相关的整个半球的严重损伤，由于其在急性计算机断层扫描上的表现，称为“半球低密度”。在SDH下的半球描绘的损伤与另一半球的显著保留是未成熟特有的损伤模式。婴儿的两个半球经常出现损伤，而幼儿更常见的是SDH对侧的半球相对完好。婴儿的氯化物梯度不成熟，可能导致亚临床癫痫发作，这可能会加剧组织损伤的程度。目前没有任何医学治疗可以阻止这种损伤的进展。理解AHT病理生理学的一个重要障碍是缺乏复制这些损伤的动物模型。在这里，我们建议在我们独特的AHT模型中测试受试者年龄的影响，该模型结合了皮质撞击、单侧硬膜下血肿、中线移位、呼吸暂停和癫痫发作，以阐明病理生理学。我们有很长的历史研究年龄依赖性差异，在响应TBI使用小猪发育可比的人类婴儿（PND 7）和幼儿（PND 30）。在这里，我们建议确定年龄对1的影响。）通过MRI和病理学确定的AHT损伤后的组织损伤模式和2.）AHT典型损伤后癫痫发作的发展。我们的中心假设是，组合的侮辱协同作用，压倒了未成熟大脑的固有补偿能力，导致更广泛的损害模式，是年龄依赖性的。损伤后病理学中年龄依赖性模式的确定和导致组织损伤（如癫痫发作和水肿）的关键成分的鉴定将产生定向治疗的靶点。中止AHT后启动的级联反应的治疗方法可能会降低神经损伤的严重程度，并减少因伤害而死亡或永久残疾的儿童数量。