Over 250,000 people in the US are currently living with disabilities related to spinal cord injury (SCI). The number of SCI's among the aging population has been steadily increasing since the 1980's, and is associated with high rates of co-morbidities. Oxidative stress and reactive oxygen species (ROS) are increased in aging tissue and have been causally implicated in tissue damage and chronic inflammation in the central nervous system (CNS). These stressors influence the activity of glial cells, contributing to the delayed recovery to SCI seen in the aging population. No work to date has examined age-related alterations in glial cell response to SCI. The NADPH oxidase (NOX) family of enzymes is suggested to play a modulatory role in microglial/macrophage activation, inflammation and tissue damage through the production of ROS, and is chronically up-regulated after SCI. NOX, microglia and astrocytes all show altered profiles with increased inflammatory morphology and basal activation states in both human and rodent aged populations. Thus, we hypothesize that age-related upregulation in NOX activity and expression leads to increased proinflammatory glial cell activation states, resulting in exaggerated glial responses and diminished recovery to spinal cord injury. To test this hypothesis, we propose three specific aims.
In aim 1, we will characterize basal glial cell activation states and NOX expression and activity in the aging rodent spinal cord. In this aim, we will use double labeled immunohistochemistry and biochemical techniques to characterize NOX and glial cell activation state in 3 and 12 month aged rats.
In aim 2, we will demonstrate the effects of aging on NOX expression and activity, glial cell activation, lesion size and functional recovery after spinal cod injury. In this aim, we will assess NOX and glial cell activation after a moderate contusion SCI in 3 and 12 month aged rats using immunohistochemistry, biochemistry, RT-qPCR and functional assessment.
In aim 3, we will evaluate the effect of inhibition of NOX activity and expression on basal glial activation and response to injury. In this aim, we will assess the modulatory effects o NOX on microglia and astrocyte activation in aged rats using a NOX2 specific inhibitor. This effect will be investigated using immunohistochemistry, biochemistry, subcellular fractionation and functional assessment. The data generated in these aims will help to guide researchers and clinicians in more effective diagnosis and may provide important insight into potential future therapeutic targets for SCI in the aging population.

Public Health Relevance

Spinal cord injury among the middle aged and elderly population (50 and older) has increased 5-fold in the last 30 years, and evidence suggests that increased oxidative stress in aging may prime glial cells at rest, leading to an exaggerated response to injury. The proposed research study will determine the effects of age on glial cell activation and response to injury, exploring age-related alterations to NADPH oxidase, a primary source of reactive oxygen species present on neural and glial cells, providing valuable data that will aid in determination of age-related effects on inflammatory response and the potential of NADPH oxidase as a therapeutic target for spinal cord injury in the aging population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS090737-01A1
Application #
9051752
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
von Leden, Ramona E; Yauger, Young J; Khayrullina, Guzal et al. (2017) Central Nervous System Injury and Nicotinamide Adenine Dinucleotide Phosphate Oxidase: Oxidative Stress and Therapeutic Targets. J Neurotrauma 34:755-764
von Leden, Ramona E; Khayrullina, Guzal; Moritz, Kasey E et al. (2017) Age exacerbates microglial activation, oxidative stress, inflammatory and NOX2 gene expression, and delays functional recovery in a middle-aged rodent model of spinal cord injury. J Neuroinflammation 14:161
von Leden, Ramona E; Selwyn, Reed G; Jaiswal, Shalini et al. (2016) (18)F-FDG-PET imaging of rat spinal cord demonstrates altered glucose uptake acutely after contusion injury. Neurosci Lett 621:126-132