J147 Treatment for Traumatic Brain Injury in Brain Damage and Long-Term Functional Recovery

J147 脑外伤治疗中的脑损伤和长期功能恢复

基本信息

批准号：
10372618
负责人：
Rong Jin
金额：
$ 44.6万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372618
关键词：
Acute Adult Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Animals Apoptosis Area Attenuated Biological Biological Availability Blood - brain barrier anatomy Body Fluids Body Weight Brain Brain Contusions Brain Injuries CASP3 gene Cause of Death Cells Child Clinical Contusions Curcumin Data Development Disease Dose Glutamates Golgi Apparatus Hippocampus (Brain)Impaired cognition Inflammation Injury Ischemic Stroke Laboratories Long-Term Effects Measurement Measures Mediating Metabolism Mitochondria Modeling Molecular Mus Nerve Degeneration Nervous System Physiology Neuronal Injury Neuronal Plasticity Neurons Operative Surgical Procedures Oral Outcome Oxidative Stress Pathway interactions Patients Permeability Phase I Clinical Trials Process Property Proteins Public Health RNA Interference Recovery Recovery of Function Role SIRT1 gene Severities Stains Stress Stroke Study Section Survival Rate Synaptic Vesicles Synaptic plasticity TBI treatment TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Translating Traumatic Brain Injury Treatment Efficacy Vertebral column Western Blotting age group age related neurodegeneration base bench to bedside controlled cortical impact density disability endoplasmic reticulum stress excitotoxicity experimental study improved improved outcome insight mouse model neurobehavioral test neurological recovery neuron loss novel novel therapeutic intervention prevent small molecule spatial temporal variation synaptogenesis white matter damage

项目摘要

ABSTRACT Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated from the bench to the clinic. In this proposal, we hypothesize that the therapeutic treatment of J147 protects against secondary brain damage and promotes long-term functional recovery following TBI. J147, a curcumin-derived small molecule compound which can easily cross the BBB, has been shown to have multiple neuroprotective and neurotrophic properties against age-related neurodegenerative disorders. In addition, J147 is shown to be neuroprotective against experimental ischemic stroke and glutamate-induced neuronal death in cortical neuron culture. However, the effects of J147 in TBI has not yet been investigated. In a mouse controlled cortical impact model of TBI, our preliminary data show that J147 treatment prevents neuronal cell degeneration and attenuates prolonged ER stress in the perilesional area after TBI. Moreover, J147 treatment significantly promotes the recovery of neurological functions during the 2-week observation period after TBI, with a substantial improvement in neuronal plasticity. These exciting preliminary data suggest that J147 treatment may represent a promising therapeutic approach to prevent and/or reduce secondary brain damage, improving long-term outcomes following TBI. In this application, we propose to develop a new TBI therapy with J147 treatment and to investigate molecular mechanisms underlying J147 therapy-mediated beneficial effects. We now propose three aims to investigate this new TBI therapy. In aim 1, we will explore the optimal dose of J147 treatment for TBI in functional recovery and injury severity. Brain contusion volume, hippocampal neuronal loss and white matter damage will be examined 35 days after brain injury. A battery of neurobehavioral tests will be performed during the 35-day survival time. In aim 2, we will explore the therapeutic time-window of J147, and its effects on long-term recovery and impacts among different ages. For exploring the therapeutic time-window, the optimal dose of J147 will be initiated 1- 12h. The animals will be allowed to survive for 35 days. For testing long-term effects of J147 and its impacts among different ages, two different age groups will be subjected to TBI and treated with J147. Animals will be allowed to survive for 6 months. All measurements will be performed similarly to Aim 1. In aim 3, we will explore the potential mechanisms underlying the J147 treatment that attenuate brain damage and promote functional recovery, with a focus on ER stress, apoptosis, and neuronal plasticity. The spatial and temporal variation of ER stress and stress-related Sirt1 activation will be assessed. The neuronal cell degeneration and apoptosis in the perilesional area will be determined. The RNAi experiment will be performed to identify the actions of J147 in the relation of Sirt1 activation with ER stress and apoptosis after TBI. The role of J147 in post-injury neuronal plasticity will also be explored.

抽象的创伤性脑损伤 (TBI) 是一个重大的临床问题，成功的治疗干预措施很少从实验室转移到诊所。在此提案中，我们假设 J147 的治疗方法防止继发性脑损伤并促进 TBI 后的长期功能恢复。 J147，一种姜黄素衍生的小分子化合物，可以轻松穿过血脑屏障，已被证明具有多种功效针对与年龄相关的神经退行性疾病的神经保护和神经营养特性。此外，J147 被证明对实验性缺血性中风和谷氨酸诱导的神经元死亡具有神经保护作用皮质神经元培养。然而，J147 在 TBI 中的作用尚未得到研究。在鼠标控制下 TBI 的皮质影响模型，我们的初步数据表明 J147 治疗可防止神经元细胞变性并减轻 TBI 后病灶周围区域的长期 ER 应激。此外，J147治疗显着在TBI后2周的观察期内促进神经功能的恢复，具有显着的效果神经元可塑性的改善。这些令人兴奋的初步数据表明 J147 治疗可能代表一种有前途的治疗方法，可以预防和/或减少继发性脑损伤，改善长期症状 TBI 后的结果。在本申请中，我们建议开发一种新的 TBI 疗法，采用 J147 治疗和研究 J147 治疗介导的有益作用的分子机制。我们现在提议三是研究这种新的 TBI 疗法。在目标 1 中，我们将探讨 J147 治疗 TBI 在功能恢复和损伤严重程度方面的最佳剂量。术后35天检查脑挫裂伤体积、海马神经元丢失和白质损伤脑损伤。在 35 天的生存时间内将进行一系列神经行为测试。在目标 2 中，我们将探讨 J147 的治疗时间窗及其对长期恢复的影响和影响不同年龄段之间。为了探索治疗时间窗口，J147 的最佳剂量将在 1- 12小时。这些动物将被允许存活35天。用于测试 J147 的长期效果及其影响不同年龄组中，两个不同年龄组将接受TBI并接受J147治疗。动物将会允许存活6个月。所有测量的执行方式与目标 1 类似。在目标 3 中，我们将探索 J147 治疗减轻脑损伤的潜在机制促进功能恢复，重点关注内质网应激、细胞凋亡和神经元可塑性。空间和将评估 ER 应激和应激相关 Sirt1 激活的时间变化。神经元细胞将确定病变周围区域的变性和细胞凋亡。将进行RNAi实验确定 J147 在 Sirt1 激活与 TBI 后 ER 应激和细胞凋亡关系中的作用。角色还将探讨 J147 在损伤后神经元可塑性中的作用。