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Identifying Potential Therapeutic Targets for Abusive Head Trauma

确定虐待性头部创伤的潜在治疗目标

基本信息

批准号：
10689076
负责人：
Beth A Costine-Bartell
金额：
$ 44.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689076
关键词：
Accident and Emergency department Accidents Acute Admission activity Age Anesthesia procedures Antiepileptic Agents Apnea Area Biological Markers Blood Vessels Brain Hypoxia-Ischemia Brain Injuries Brain region Characteristics Child Childhood Childhood Injury Clinical Clinical Management Contralateral Craniocerebral Trauma Critical Care Depressed mood Development Disabled Persons Elements Event Evolution Focal Seizure Functional disorder Future Goals Guidelines Hemorrhage Hospitalization Hospitals Hour Human Hypoventilation Image Impairment Infant Injury Intensive Care Kainic Acid Location Matrix Metalloproteinases Mechanics Metabolic acidosis Modeling Multiple Trauma Neurologic Neurological status Outcome Pattern Pediatric Intensive Care Units Protocols documentation Radiology Specialty Seizures Severities Shaken baby syndrome Subarachnoid Hemorrhage Subdural Hematoma Testing Therapeutic Time Tissues Toddler Trauma Traumatic Brain Injury Up-Regulation X-Ray Computed Tomography age related brain morphology cerebral atrophy clinically relevant disability burden hemisphere damage innovation mortality neural permissiveness prevent severe injury therapeutic target therapy development time interval tissue trauma vasogenic edema

项目摘要

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.

项目总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury.

DOI：
10.1093/pnasnexus/pgad434
发表时间：
2024-01
期刊：
PNAS NEXUS
影响因子：
0
作者：
Kapate, Neha;Liao, Rick;Sodemann, Ryan Luke;Stinson, Tawny;Prakash, Supriya;Kumbhojkar, Ninad;Suja, Vineeth Chandran;Wang, Lily Li-Wen;Flanz, Mikayla;Rajeev, Rohan;Villafuerte, Dania;Shaha, Suyog;Janes, Morgan;Park, Kyung Soo;Dunne, Michael;Golemb, Bryan;Hone, Alexander;Adebowale, Kolade;Clegg, John;Slate, Andrea;McGuone, Declan;Costine-Bartell, Beth;Mitragotri, Samir
通讯作者：
Mitragotri, Samir

A perfect storm: The distribution of tissue damage depends on seizure duration, hemorrhage, and developmental stage in a gyrencephalic, multi-factorial, severe traumatic brain injury model.