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）：我的目标是成为儿童虐待性头部创伤 (AHT) 方面唯一合格、高产、独立的生物医学研究者。具体来说，我对研究儿童损伤的演变以及对此类损伤进行建模感兴趣。仔猪开发针对年龄和损伤的特定治疗方法，这些治疗方法将转化为针对婴儿和儿童的有效治疗方法，以减轻损伤后发病率和死亡率的负担，需要了解导致观察到的广泛损伤模式的病理生理级联反应。目前，尽管临床、放射学、生物力学和病理学观察中存在线索，但对儿童 AHT 的病理生理学知之甚少，我将首先重点研究在我们独特的不成熟的大型儿童中，损伤和侮辱后 AHT 特征的年龄依赖性病理生理学。尽管我拥有丰富的基础神经科学经验，并且在 Duhaime 博士的转化实验室中研究了意外的儿科头部创伤，但直到最近不断增加的临床接触，我才意识到这种普遍存在的现象。为了在我未来的独立职业生涯中准确地模拟 AHT，我要求对临床虐待头进行额外的多学科培训。 通过哈佛医学院的课程、国内和国际会议、法医观察病理学船以及 Duhaime、Newton 和 McGuone 博士的培训，他们正在对 AHT 儿童进行教​​学和研究（临床）。通过 MRI 或尸检进行的演示、损伤演变和结果指标）将允许 我的目的是更准确地模拟、描述和解释仔猪的这种复杂损伤，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，并且可能导致病理生理级联反应。为了研究癫痫发作在 AHT 后加剧损伤中的潜在作用，我请求 Staley 博士进行培训，他是电图癫痫发作检测、离子传输和治疗方面的世界领先者。通过哈佛大学的课程，我将了解未成熟大脑中细胞毒性脑水肿的基本病理生理学，这是研究受伤儿童和观察我们的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学习寻求培训，亨特博士是使用 MRI 研究儿童头部损伤的世界权威，我以前在儿童意外脑损伤领域拥有丰富的经验。创伤，我的导师和合作者团队，以及麻省总医院/哈佛大学/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，阐明这些神秘而不幸的常见创伤性脑损伤。儿童死亡和残疾的主要原因是 2 岁以下儿童。 尽管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，这是由严重损伤引起的最常见的颅内异常。呼吸暂停发作时，组织损伤不仅限于 SDH 正下方的区域，而是局部受损的实质组织，在严重的情况下，损伤可能演变成整个组织的严重损伤。与硬膜下血肿相关的半球，因其在急性计算机断层扫描中出现而被称为“半球低密度”，SDH 下方的半球描绘出的损伤，而另一半球却没有明显受损，这是一种未成熟婴儿特有的损伤模式，而婴儿的两个半球通常都出现损伤。幼儿更常见的是 SDH 对侧半球相对较少。婴儿的氯化物梯度不成熟，可能导致亚临床癫痫发作可能会加剧组织损伤，目前尚无药物可以阻止这种损伤的进展，了解 AHT 病理生理学的一个重大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，该模型结合了皮质冲击、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。使用与人类婴儿（PND 7）和幼儿（PND 30）发育相当的仔猪来研究 TBI 反应的年龄依赖性差异有着悠久的历史。在这里，我们建议确定年龄对 1.) 组织损伤模式的影响。 MRI 和病理学确定的 AHT 损伤后，以及 2.) AHT 典型损伤后癫痫发作的发生。确定损伤后的年龄依赖性病理模式，并识别导致癫痫和水肿等组织损伤的关键成分，将为定向治疗提供目标。中止 AHT 后启动的级联反应可能会减轻神经损伤的严重程度，并减少因受伤而死亡或永久残疾的儿童数量。