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

基本信息

批准号：
10676967
负责人：
Forrest M Kievit
金额：
$ 43.94万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676967
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 Learning Lipid Peroxidation Magnetic Resonance Imaging Mediating Mediator Monitor Mus Nanotechnology Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neurons Neuroprotective Agents Outcome Oxidative Stress Oxygen Pathology Penetration 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 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 long term recovery 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

项目摘要

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.

项目概要/摘要创伤性脑损伤 (TBI) 是 45 岁以下人群残疾和死亡的主要原因全球每年约有 1000 万新病例。 TBI 的影响可能很严重，包括神经认知、身体和心理社会障碍。仍有大量未满足的开发需求避免 TBI 造成长期损害的策略。 TBI 的初级阶段描述了即刻神经元全球质量效应造成的挫伤或缺氧造成的损害。继发性损伤随后发生再灌注损伤、迟发性皮质水肿、血脑屏障（BBB）破坏等机制局部电解质不平衡。这些干扰会导致活性氧 (ROS)、钙离子增加释放、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。这样的继发性损伤可能发生在邻近最初假定损伤部位的大脑中，从而产生意外的扩散受伤后数月内受损区域的情况。以治疗继发性脑损伤为目标，ROS清除剂和LP产物抑制剂已成为越来越受欢迎。然而，仍然没有有效的治疗方案可以证明改善的结果在一项大型多中心 III 期试验中，这可能部分归因于药物递送和保留不良脑。我们的总体目标是使用 ROS 和 LP 产品减少 TBI 的长期继发性损伤阶段反应性纳米颗粒（NP）可以快速积累并保留在受损组织中，以减少后遗症创伤性氧化应激。我们之前开发了有助于成像的多功能反应性纳米颗粒损伤内的分布，从而减少小鼠的神经炎症和神经行为缺陷 TBI 模型。我们假设 NP 介导的 TBI 中氧化应激的减少将减少长期损伤并改善恢复。这是基于 ROS 和 LP 所显示的临床前功效的科学前提产品抑制剂以及 NP 在 TBI 中的积累和保留。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 NP，以最大限度地提高受损大脑中的吸收和保留目标 1 中的 TBI 受控皮质冲击小鼠模型。在目标 2 中，我们将研究 NP 介导的效应减少创伤后氧化应激对继发性损伤扩散的影响，这将为我们提供治疗方法这些 NP 的索引，然后在目标 3 中测试神经行为结果。该提案利用了纳米技术的进步促进了 TBI 治疗和成像新方法的开发。如果成功后，这些 NP 可以进一步开发用于涉及进行性进展的其他病理学神经炎症和神经变性。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury.

治疗诊断共聚物中和活性氧和脂质过氧化产物，用于联合治疗创伤性脑损伤。

DOI：
发表时间：
2022-04-11
期刊：
影响因子：
6.2
作者：
Priester, Aaron;Waters, Richard;Abbott, Ashleigh;Hilmas, Krista;Woelk, Klaus;Miller, Hunter A;Tarudji, Aria W;Gee, Connor C;McDonald, Brandon;Kievit, Forrest M;Convertine, Anthony J
通讯作者：
Convertine, Anthony J

An updated Barnes maze protocol for assessing the outcome of controlled cortical impact mouse models of traumatic brain injury.

更新的巴恩斯迷宫协议，用于评估创伤性脑损伤的受控皮质冲击小鼠模型的结果。

DOI：
发表时间：
2023-05-15
期刊：
影响因子：
3
作者：
Gee, Connor C;Steffen, Rylie;Kievit, Forrest M
通讯作者：
Kievit, Forrest M

Design and Evaluation of an In Vitro Mild Traumatic Brain Injury Modeling System Using 3D Printed Mini Impact Device on the 3D Cultured Human iPSC Derived Neural Progenitor Cells.

在 3D 培养的人类 iPSC 衍生神经祖细胞上使用 3D 打印迷你冲击装置设计和评估体外轻度创伤性脑损伤建模系统。

DOI：
发表时间：
2021-06
期刊：
影响因子：
10
作者：
Shi, Wen;Dong, Pengfei;Kuss, Mitchell A;Gu, Linxia;Kievit, Forrest;Kim, Hyung Joon;Duan, Bin
通讯作者：
Duan, Bin

Antioxidant theranostic copolymer-mediated reduction in oxidative stress following traumatic brain injury improves outcome in a mouse model.

抗氧化治疗诊断共聚物介导的创伤性脑损伤后氧化应激的减少可改善小鼠模型的结果。

DOI：
发表时间：
2023-12
期刊：
影响因子：
4.6
作者：
Tarudji, Aria W;Gee, Connor C;Miller, Hunter A;Steffen, Rylie;Curtis, Evan T;Priester, Aaron M;Convertine, Anthony J;Kievit, Forrest M
通讯作者：
Kievit, Forrest M

The Nanotheranostic Researcher's Guide for Use of Animal Models of Traumatic Brain Injury.

纳米治疗研究人员使用创伤性脑损伤动物模型的指南。