Trauma to developing brain: model refinement and therapeutic intervention

大脑发育创伤：模型完善和治疗干预

基本信息

批准号：
7906818
负责人：
HARVEY LEVIN
金额：
$ 18.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906818
关键词：
4 year old Academic achievement Acute Adaptive Behaviors Address Adolescence Adolescent Adult Adverse effects Age Amyloid beta-Protein Precursor Animal Model Animals Arts Attention Biological Assay Biological Preservation Blood - brain barrier anatomy Brain Brain Injuries Brain imaging Brain region Cause of Death Cessation of life Child Childhood Childhood Injury Clinical Clinical Data Clinical assessments Cognition Cognitive Cognitive deficits Corpus Callosum Data Demyelinations Development Diffuse Diffusion Magnetic Resonance Imaging Dose Environment Extracellular Matrix Family Gray unit of radiation dose Hippocampus (Brain)Human Image Imaging Techniques Impaired cognition Impairment In Situ Nick-End Labeling Inflammation Injury Innovative Therapy Lead Learning Lesion Long-Term Effects Magnetic Resonance Imaging Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Memory Modeling Morbidity - disease rate Morphogenesis Motor Skills Mus Myelin Basic Proteins Neuronal Injury Neurons Outcome Pathogenesis Pathologic Pathology Peptide Hydrolases Personal Satisfaction Pharmaceutical Preparations Population Public Health Research Structure Techniques Testing Therapeutic Intervention Time Tissues Toddler Translational Research Trauma Traumatic Brain Injury X-Ray Computed Tomography base brain volume cell injury clinically relevant cognitive function critical period design disability effective therapy follow-up functional status gray matter hippocampal subregions improved injured morris water maze mortality motor deficit mouse model myelination neuron loss neuroprotection novel postnatal rapid growth relating to nervous system repaired virtual way finding white matter white matter damage young adult

项目摘要

Traumatic brain injury (TBI) is the most frequent cause of acquired brain injury, mortality, and morbidity in young children. A key obstacle to improved outcome of pediatric TBI is the paucity of translational research to identify innovative therapy. Here we address this obstacle by validating a murine model of trauma to the immature brain using clinically relevant measures, as defined in parallel studies in a pediatric population, and consider the efficacy of a matrix metalloproteinase (MMP) inhibitor in maintaining long-term grey and white matter integrity and preserving cognitive development after experimental TBI. In Specific Aim 1, using long term follow-up of 26 adolescents who sustained moderate to severe TBI at age 2-4 years, we propose brain imaging techniques to measure brain region volumes and white matter integrity at adolescence, focusing on the cortex, hippocampus and corpus callosum, structures that show acute damage in both animal models and children. Using a virtual maze task analogous to the Morris Water Maze employed to measure memory in our murine model, we will assess navigation and spatial memory in the adolescents who sustained early TBI. To assess the effects of frontal, temporal, and diffuse pathology, we will evaluate executive cognitive functions and overall functional status in the adolescents and analyze the relation of brain imaging findings to the cognitive outcome data. In Specific Aim 2, mice at postnatal day (pnd) 21 will be subjected to TBI and treated thereafter with the MMP inhibitor GM6001. We will first define an optimal dose and timing of administration of this drug based upon subacute anatomical measures of neuroprotection. We will then determine if this optimal dose/timing improves longer-term outcomes in mid and late adolescent mice who sustained injury at pnd 21. Stereologic and functional assays, designed to parallel the clinical measures in Aim 1, will be used to assess the consequences of treatment on cortex, hippocampus, and corpus callosum volumes and preservation of hippocampal neuronal populations, and to evaluate cognitive function using the Morris Water Maze. At the completion of these studies, we will have evaluated the efficacy of GM6001 in an animal model of TBI using outcomes validated in the pediatric population, a necessary first step toward advancing treatment of acute TBI in young children and mitigating the long term effects on cognitive development. Moreover, our introduction of measuring navigation and spatial memory to test hippocampal function in adolescents who sustained early TBI could also potentially advance clinical assessment techniques in this population.

创伤性脑损伤 (TBI) 是幼儿获得性脑损伤、死亡和发病的最常见原因。改善儿科 TBI 结局的一个主要障碍是缺乏确定创新疗法的转化研究。在这里，我们通过使用临床相关措施验证未成熟大脑创伤的小鼠模型来解决这一障碍，如儿科人群的平行研究中所定义，并考虑基质金属蛋白酶（MMP）抑制剂在维持长期灰白和实验性 TBI 后白质完整性和保持认知发育。在具体目标 1 中，通过对 26 名在 2-4 岁时遭受中度至重度 TBI 的青少年进行长期随访，我们提出了脑成像技术来测量青春期的大脑区域体积和白质完整性，重点关注皮质、海马体和胼胝体，这些结构在动物模型和儿童中都显示出严重损伤。使用类似于莫里斯水迷宫的虚拟迷宫任务来测量小鼠模型中的记忆，我们将评估遭受早期 TBI 的青少年的导航和空间记忆。为了评估额叶、颞叶和弥漫性病理学的影响，我们将评估青少年的执行认知功能和整体功能状态，并分析脑成像结果与认知结果数据的关系。在具体目标 2 中，小鼠在出生后第 21 天（pnd）将接受 TBI，然后用 MMP 抑制剂 GM6001 进行治疗。我们将首先根据神经保护的亚急性解剖学措施确定该药物的最佳剂量和给药时间。然后，我们将确定这种最佳剂量/时间是否可以改善在第 21 年遭受损伤的青春期中期和晚期小鼠的长期结果。旨在与目标 1 中的临床措施平行的体视学和功能测定将用于评估后果对皮层、海马体和胼胝体体积的治疗和海马神经元群的保存，并使用莫里斯水迷宫评估认知功能。这些研究完成后，我们将使用在儿科人群中验证的结果来评估 GM6001 在 TBI 动物模型中的疗效，这是推进幼儿急性 TBI 治疗并减轻对认知的长期影响的必要的第一步。发展。此外，我们引入测量导航和空间记忆来测试遭受早期 TBI 的青少年的海马功能，也可能会推进该人群的临床评估技术。

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）

Developmental Alterations in Cortical Organization and Socialization in Adolescents Who Sustained a Traumatic Brain Injury in Early Childhood.

童年早期遭受创伤性脑损伤的青少年皮质组织和社会化的发育变化。

DOI：
发表时间：
2021
期刊：
影响因子：
4.2
作者：
Wilde, Elisabeth A;Merkley, Tricia L;Lindsey, Hannah M;Bigler, Erin D;Hunter, Jill V;Ewing;Aitken, Mary E;MacLeod, Marianne C;Hanten, Gerri;Chu, Zili D;Abildskov, Tracy J;Noble;Levin, Harvey S
通讯作者：
Levin, Harvey S

Ten-year outcome of early childhood traumatic brain injury: Diffusion tensor imaging of the ventral striatum in relation to executive functioning.

儿童早期创伤性脑损伤的十年结果：与执行功能相关的腹侧纹状体的扩散张量成像。

DOI：
发表时间：
2016
期刊：
影响因子：
1.9
作者：
Faber, J;Wilde, E A;Hanten, G;Ewing;Aitken, M E;Yallampalli, R;MacLeod, M C;Mullins, S H;Chu, Z D;Li, X;Hunter, J V;Noble;Levin, H S
通讯作者：
Levin, H S

Acute pediatric traumatic brain injury severity predicts long-term verbal memory performance through suppression by white matter integrity on diffusion tensor imaging.

急性小儿创伤性脑损伤的严重程度通过扩散张量成像的白质完整性抑制来预测长期言语记忆表现。

DOI：
发表时间：
2020-10
期刊：
影响因子：
0
作者：
Lindsey, Hannah M;Lalani, Sanam J;Mietchen, Jonathan;Gale, Shawn D;Wilde, Elisabeth A;Faber, Jessica;MacLeod, Marianne C;Hunter, Jill V;Chu, Zili D;Aitken, Mary E;Ewing;Levin, Harvey S
通讯作者：
Levin, Harvey S