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

Award Number: R01NS109488
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$14,722 )
2026	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST # 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/10/2026	NON-COMPETING CONTINUATION	-$14,722
														Subtotal = -$14,722

Issue Date FY: 2023 ( Subtotal = $439,444 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST BOX 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/20/2023	NON-COMPETING CONTINUATION	$439,444
														Subtotal = $439,444

Issue Date FY: 2022 ( Subtotal = $437,232 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST BOX 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/4/2022	NON-COMPETING CONTINUATION	$437,232
														Subtotal = $437,232

Issue Date FY: 2021 ( Subtotal = $446,587 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST BOX 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/19/2021	NON-COMPETING CONTINUATION	$446,587
														Subtotal = $446,587

Issue Date FY: 2020 ( Subtotal = $445,684 )
2020	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST BOX 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/23/2020	NON-COMPETING CONTINUATION	$445,684
														Subtotal = $445,684

Issue Date FY: 2019 ( Subtotal = $447,459 )
2019	2019	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	2200 VINE ST BOX 830861	LINCOLN	NE	68503	LANCASTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/26/2019	NEW	$447,459
														Subtotal = $447,459

Grand Total All Awards = $2,201,684

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

Award Number: R01NS109488

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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