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Principal Investigator: Forrest M Kievit
Organization: UNIVERSITY OF NEBRASKA LINCOLN
Fiscal Year: 2019
Award: $447,459
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <2-Propenal><4 hydroxynonenal><4-HNE cpd><4-hydroxy-2,3-nonenal><4-hydroxy-2-nonenal><4-hydroxynonen-2-al><Acquired brain injury><Acraldehyde><Acrolein><Acrylaldehyde><Acrylic Aldehyde><Active Oxygen><Address><Affect><Allyl Aldehyde><Antioxidants><Behavior><Biochemical><Biological><Blood - brain barrier anatomy><Blood-Brain Barrier><Body Tissues><Brain><Brain Injuries><Brain Nervous System><Brain Trauma><Bruise><Calcium><Cellular Infiltration><Cessation of life><Chemistry><Clinical><Complex><Contrast Agent><Contrast Drugs><Contrast Media><Contusions><Death><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Dropsy><Edema><Electrolytes><Encephalon><Ethylene Aldehyde><Event><Feedback><Formulation><Gadolinium><Gd element><Glutamates><Goals><Hemato-Encephalic Barrier><Hydrops><Image><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impairment><Injury><Ischemia-Reperfusion Injury><L-Glutamate><Lead><Lipid Peroxidation><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Monitor><Murine><Mus><NMR Imaging><NMR Tomography><Nanotechnology><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocognitive><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Neuroprotectants><Neuroprotective Agents><Neuroprotective Drugs><Nuclear Magnetic Resonance Imaging><O element><O2 element><Outcome><Oxidative Stress><Oxygen><Oxygen Radicals><Pathology><Pb element><Performance><Phase><Pro-Oxidants><Property><Radiopaque Media><Reactive Oxygen Species><Recovery><Reperfusion Damage><Reperfusion Injury><Series><Site><Stress><Testing><Therapeutic><Therapeutic Index><Time><Tissues><Toxic effect><Toxicities><Traumatic Brain Injury><Treatment Efficacy><Work><Zeugmatography><acryaldehyde><anti-oxidant><base><behavior outcome><behavior test><behavioral outcome><behavioral test><brain damage><brain tissue><brain-injured><controlled cortical impact><cross-link><crosslink><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><deprivation><design><designing><developmental><disability><effective therapy><effective treatment><functional outcomes><glutamatergic><heavy metal Pb><heavy metal lead><image guidance><image guided><imaging><improved><improved outcome><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><intervention efficacy><learning activity><learning method><learning strategy><mitochondrial dysfunction><mouse model><murine model><nano particle><nano particle delivery><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotech><nanotechnological><neural degeneration><neurobehavioral><neurobehavioral test><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuroprotection><new approaches><novel approaches><novel strategies><novel strategy><phase III trial><pre-clinical efficacy><preclinical efficacy><prevent><preventing><psychosocial><success><therapeutic efficacy><therapeutically effective><therapy efficacy><traumatic brain damage><treatment effect><uptake>