Pathology-directed combination therapy for pediatric TBI

儿科 TBI 的病理导向联合治疗

基本信息

批准号：
8308568
负责人：
Ramesh Raghupathi
金额：
$ 27.7万
依托单位：
DREXEL UNIVERSITY
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：
2009-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308568
关键词：
4 year old Action Potentials Acute Adult Affect Age Animals Anti-Inflammatory Agents Anti-inflammatory Apoptotic Attenuated Behavioral Biochemical Brain Calcineurin Calcineurin inhibitor Calpain Caring Caspase Cell Death Child Child Mortality Childhood Chronic Clinical Clinical Trials Closed head injuries Cognitive Cognitive deficits Combined Modality Therapy Data Dose Drug Compounding Emotional Excitatory Amino Acid Antagonists FK506 Failure Gliosis Health Hour Immunophilins Individual Infant Inflammation Inflammatory Injury Insulin-Like Growth Factor I Intervention Learning Life Ligands Literature Magic Mediating Memory impairment Microglia Modeling Morbidity - disease rate Nerve Degeneration Outcome Pathologic Pathology Pathway interactions Patients Phase Population Property Protein Dephosphorylation Rattus Severities Somatomedins Staging Survivors Testing Therapeutic Tissues Toddler Trauma Traumatic Brain Injury United States Work abstracting axonal degeneration base caspase-3 clinically relevant cytokine disability functional outcomes immature animal improved inhibitor/antagonist injured mature animal mortality neurofilament neuron loss pediatric traumatic brain injury preclinical study research study social treatment strategy

项目摘要

Abstract Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in infants and children under the age of 4. As in the case of older children and adults, the spectrum of injury severity spans the gamut from mild to severe, with mild-moderate injured patients being the predominant population. In addition, increased efficacy of supportive neurointensive care has significantly reduced the mortality. Collectively, these phenomena result in an increasing number of survivors of TBI, who are faced with suffering life-long cognitive, emotional and social deficits. Although the pathologic alterations (cell death, axonal injury, reactive gliosis and inflammation) following closed head injury appears to be similar in both the mature and immature brains, clinical and animal studies are beginning to demonstrate the pathogenic mechanisms in the acute and chronic post-traumatic periods are fairly dissimilar between the two ages. A second problem is that acute neuroprotective strategies, the mainstay of clinical trials and pre-clinical studies, are focused on a single "magic bullet" approach despite the multitude of pathogenic mechanisms, setting the stage for failure in clinical trials. This proposal therefore, seeks to fill these two gaps in the TBI literature by using an age-appropriate, clinically-relevant model of pediatric TBI and testing whether two strategies, each aimed at limiting distinctly separate pathologic pathways, when combined, will improve functional outcome. The 17-day-old rat which is neurologically equivalent to 3-4-year-old toddler is the animal of choice. The choice of these two strategies in the current proposal arises from preliminary observations that the calcineurin inhibitor and immunophilin ligand, FK506, attenuates traumatic axonal injury following closed head injury in immature rat. In separate experiments, it was observed that the anti-inflammatory and anti-apoptotic tripeptide, Glypromate - derived endogenously from the N-terminus of insulin-like growth factor - reduced microglial activation, tissue calpain activation and attendant neurodegeneration. Using a combination of biochemical, immunohistochemical, electrophysiologic and behavioral analyses, the hypothesis to be tested is that FK506, by inhibiting calcineurin- mediated neurofilament compaction and decreasing axonal injury, in combination with Glypromate which will inhibit microglial activation, decrease cytokine synthesis and reduce neurodegeneration, will together reduce acute and chronic learning and memory deficits in the brain-injured immature rat.

抽象的创伤性脑损伤（TBI）是婴儿和婴儿发病和死亡的主要原因之一 4 岁以下的儿童。与年龄较大的儿童和成人一样，伤害严重程度范围广泛范围从轻度到重度，其中轻度至中度受伤的患者是主要人群。在此外，支持性神经重症监护疗效的提高显着降低了死亡率。总的来说，这些现象导致越来越多的 TBI 幸存者面临着痛苦终生的认知、情感和社交缺陷。尽管病理改变（细胞死亡、轴突损伤、闭合性头部损伤后的反应性神经胶质增生和炎症）在成熟和不成熟的大脑，临床和动物研究开始证明其致病机制这两个年龄段的急性和慢性创伤后时期相当不同。第二个问题是急性神经保护策略是临床试验和临床前研究的支柱，集中于单一的尽管致病机制众多，但“灵丹妙药”方法为临床失败奠定了基础试验。因此，本提案旨在通过使用适合年龄的、儿科 TBI 的临床相关模型，并测试是否有两种策略，每种策略都旨在明显限制单独的病理途径结合起来将改善功能结果。 17天大的老鼠是神经学上相当于3-4岁幼儿的动物是首选动物。这两种策略的选择目前的提议源于钙调神经磷酸酶抑制剂和亲免素配体的初步观察， FK506 可减轻未成熟大鼠闭合性头部损伤后的创伤性轴索损伤。在单独的实验中发现，Glypromate 衍生的三肽具有抗炎和抗凋亡作用来自胰岛素样生长因子 N 末端的内源性 - 减少小胶质细胞活化、组织钙蛋白酶激活和随之而来的神经变性。结合使用生化、免疫组织化学、电生理学和行为分析，要测试的假设是 FK506 通过抑制钙调神经磷酸酶与 Glypromate 结合，介导神经丝压实并减少轴突损伤抑制小胶质细胞活化，减少细胞因子合成并减少神经退行性变，将共同减少脑损伤的未成熟大鼠的急性和慢性学习和记忆缺陷。