Nanoparticle-mediated reduction of oxidative stress for the treatment of traumatic brain injury

纳米颗粒介导的氧化应激减少治疗创伤性脑损伤

• 批准号: 10454334
• 负责人: Forrest M Kievit
• 金额: $ 43.72万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454334
• 关键词: 4 hydroxynonenal; Acrolein; Address; Affect; Antioxidants; Behavior; Biochemical; Biological; Blood - brain barrier anatomy; Brain; Brain Injuries; Calcium; Cellular Infiltration; Cessation of life; Chemistry; Clinical; Complex; Contrast Media; Contusions; Development; Edema; Electrolytes; Event; Feedback; Formulation; Gadolinium; Glutamates; Goals; Image; Immunologics; Impairment; Injury; Lead; Lipid Peroxidation; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Monitor; Mus; Nanotechnology; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Outcome; Oxidative Stress; Oxygen; Pathology; Performance; Persons; Phase; Property; Reactive Oxygen Species; Recovery; Reperfusion Injury; Series; Site; Stress; TBI treatment; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Traumatic Brain Injury; Treatment Efficacy; Work; base; behavior test; behavioral outcome; brain tissue; controlled cortical impact; crosslink; delivery vehicle; deprivation; design; disability; effective therapy; functional outcomes; image guided; improved; improved outcome; inhibitor; innovation; learning strategy; mitochondrial dysfunction; mouse model; nanoparticle; nanoparticle delivery; neurobehavioral; neurobehavioral test; neuroinflammation; neuroprotection; novel strategies; phase III trial; preclinical efficacy; prevent; psychosocial; success; treatment effect; uptake

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of disability and death in people under 45 with approximately 10 million new cases each year worldwide. The effects of TBI can be severe, including neurocognitive, physical, and psychosocial impairment. There remains a significant unmet need to develop strategies to avoid long-term damage from TBI. The primary phase of TBI describes immediate neuronal damage from contusions or oxygen deprivation caused by global mass effect. Secondary injury occurs later via such mechanisms as reperfusion injury, delayed cortical edema, blood-brain barrier (BBB) breakdown, and local electrolyte imbalance. These disturbances result in increased reactive oxygen species (ROS), calcium release, glutamate toxicity, lipid peroxidation (LP), and mitochondrial dysfunction that lead to a vicious positive feedback loop of progressive oxidative stress-mediated neurodegeneration and neuroinflammation. Such secondary injury may occur in brain adjacent to the site of initial supposed injury, yielding unexpected spread of the zone of damage over months post-injury. With the goal of treating secondary brain injury, ROS scavengers and LP product inhibitors have become increasingly popular. However, there are still no effective treatment options demonstrating improved outcome in a large, multi-center Phase III trial, which can be partially attributed to poor delivery to and retention in the brain. Our overall goal is to reduce the long-term secondary injury phase of TBI using ROS and LP product reactive nanoparticles (NPs) that can quickly accumulate and be retained in damaged tissue to reduce post- traumatic oxidative stress. We have previously developed multifunctional, reactive NPs that aid in imaging distribution within the injury and result in reduced neuroinflammation and neurobehavioral deficits in a mouse model of TBI. We hypothesize that NP-mediated reduction oxidative stress in TBI will reduce long-term damage and improve recovery. This is based on the scientific premise of preclinical efficacy shown with ROS and LP product inhibitors as well as NP accumulation and retention in a TBI. To address our hypothesis, we will refine and optimize our modular, image-guided NPs to maximize uptake and retention within damaged brain in a controlled cortical impact mouse model of TBI in Aim 1. In Aim 2, we will study the effects of NP-mediated reduction in post-traumatic oxidative stress on the spread of secondary injury that will provide us a therapeutic index for these NPs and, and then in Aim 3 test neurobehavioral outcome. This proposal capitalizes on advances in nanotechnology that facilitate the development of novel approaches to treat and image TBI. If successful, these NPs could be further developed for other pathologies that involve progressive neuroinflammation and neurodegeneration.

项目摘要/摘要 创伤性脑损伤（TBI）是45岁以下患者残疾和死亡的主要原因 全球每年约有1000万个新案件。 TBI的影响可能很严重，包括 神经认知，身体和社会心理障碍。仍有很大的发展需要 避免TBI长期损害的策略。 TBI的主要阶段描述了直接神经元 由全球质量效应造成的挫伤或脱氧损害。继发性伤害以后发生 再灌注损伤，延迟皮质水肿，血脑屏障（BBB）分解和等机制 局部电解质不平衡。这些干扰导致活性氧（ROS），钙增加 释放，谷氨酸毒性，脂质过氧化（LP）和线粒体功能障碍，导致恶性阳性 进行性氧化应激介导的神经变性和神经炎症的反馈回路。这样的 第二次损伤可能发生在最初假定伤害部位附近的大脑中，从而产生意外扩散 伤害后几个月的损害区域。 为了治疗继发性脑损伤，ROS ROS清除剂和LP产品抑制剂已成为 越来越受欢迎。但是，仍然没有有效的治疗方案证明结果改善 在一项大型多中心III期试验中，这可能部分归因于交付不良，并保留在 脑。我们的总体目标是使用ROS和LP产品减少TBI的长期继发阶段 反应性纳米颗粒（NP）可以迅速积累并保留在受损组织中，以减少后 创伤性氧化应激。我们以前已经开发了多功能的反应性NP，有助于成像 在损伤内分布，导致小鼠神经炎症和神经性缺陷减少 TBI的模型。 我们假设NP介导的TBI中的减少氧化应激将减少长期损害，并且 改善恢复。这是基于ROS和LP显示的临床前功效的科学前提 产品抑制剂以及NP的积累和在TBI中的保留。为了解决我们的假设，我们将完善 并优化我们的模块化，图像引导的NP，以最大程度地提高摄取和保留率 AIM 1中TBI的受控皮质冲击模型。在AIM 2中，我们将研究NP介导的效果 减少因继发性损伤传播的创伤后氧化应激，这将为我们提供治疗 这些NP的索引，然后在AIM 3测试神经行为结果。该提案大写 纳米技术的进步，促进了新颖的治疗和图像TBI的发展。如果 成功，这些NP可以进一步开发用于涉及渐进性的其他病理 神经炎症和神经变性。