Spinal cord injury (SCI) causes not only in sensorimotor deficits, but also in a chronic, severe and often unrelenting pain (SCI-pain) that occurs in as many as 85% of patients. SCI-pain has neuropathic features and is often resistant to conventional pain therapy. The latter may reflect, in part, an incomplete understanding of injury mechanisms. Identifying mechanisms responsible for post-injury neuropathic pain could provide targets for more effective therapeutic interventions. We identified a promising new therapeutic target trkB.T1, a truncated isoform of the brain-derived neurotrophic factor receptor?tropomyosin related kinase B (trkB). In mouse models of neuropathic pain including SCI, genetic deletion of trkB.T1 reduces both mechanical and thermal hypersensitivity. However, the precise cellular mechanisms underlying this finding are not fully understood. The purpose of this study is to investigate how trkB.T1 drives post-injury neuropathic pain via astrocyte dysfunction and test the hypothesis that astrocytic trkB.T1 functions as a key mechanism in post- injury reactive astrogliosis, through altered transcriptional programming that controls cellular movement and immune function, thus affecting chronic pain after spinal cord injury. We will use astrocytic trkB.T1 knock out (KO), Nox2 KO, and trkB.T1-KFG knock in transgenic mice and in vivo and in vitro innovatively technologies to determine the mechanisms of SCI-triggered trkB.T1 elevation on post- injury hyperpathia.
Aim 1 will determine the function and mechanisms of the trkB.T1/[Ca2+]i/Nox2 pathway in astrocytes after SCI. Multiple quantitative assessments of astrogliosis will be combined with a genetic intervention targeting trkB.T1 to test the hypothesis that SCI-triggered trkB.T1 elevation in astrocytes increases [Ca2+]i and Nox2 activity, contributing to neuroinflammation and hyperpathia.
Aim 2 will elucidate the role of astrocytic Nox2 signaling in post-injury hyperpathia. We will utilize genetic intervention to delete trkB.T1-dependent up-regulation of Nox2 in astrocytes, and evaluate the effects on astrocytic Nox2 on neuropathic pain after SCI.
Aim 3 will determine the role for the KFG domain on trkB.T1 in the regulation of astrocyte function and SCI-Pain. Complimentary cellular, molecular, and genetic approaches will be used to test the hypothesis that KFG domain of trkB.T1 regulates trkB.T1 function in response to BDNF, and mutation of KFG domain abolishes post-injury neuropathic pain. Our study will be the first to implicate astrocytic trkB.T1-mediated [Ca2+]i/Nox2 signaling in the pathophysiology of SCI. Our data should establish that second messenger binding to the intracellular KFG domain on trkB.T1 is a physiologically important mechanism that regulates trkB.T1-mediated pain signaling. These observations may lead to novel therapeutic targets for neuropathic pain in a wide range of disease states.

Public Health Relevance

Spinal cord injury (SCI) causes a chronic, severe and often unrelenting pain (SCI-pain) that occurs in as many as 85% of patients. It has neuropathic features and is often resistant to conventional pain therapy. The aim of our research is to understand the mechanisms responsible for post-injury neuropathic pain in order to allow future development of novel therapies. In particular, we will target the signaling pathway of trkB.T1, a truncated isoform of the brain-derived neurotrophic factor (BDNF) receptor?tropomyosin related kinase B (trkB), in order to decrease damage and increase functional recovery after SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR013601-07
Application #
9564208
Study Section
Nursing and Related Clinical Sciences Study Section (NRCS)
Program Officer
Hamlet, Michelle R
Project Start
2012-03-21
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Nursing
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Liu, Shuo; Li, Yun; Choi, Harry M C et al. (2018) Lysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosis. Cell Death Dis 9:476
Matyas, Jessica J; O'Driscoll, Cliona M; Yu, Laina et al. (2017) Truncated TrkB.T1-Mediated Astrocyte Dysfunction Contributes to Impaired Motor Function and Neuropathic Pain after Spinal Cord Injury. J Neurosci 37:3956-3971
Starkweather, Angela R; Heineman, Amy; Storey, Shannon et al. (2016) Methods to measure peripheral and central sensitization using quantitative sensory testing: A focus on individuals with low back pain. Appl Nurs Res 29:237-41
Wu, Junfang; Zhao, Zaorui; Zhu, Xiya et al. (2016) Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury. Pain 157:488-503
Starkweather, Angela R; Lyon, Debra E; Kinser, Patricia et al. (2016) Comparison of Low Back Pain Recovery and Persistence: A Descriptive Study of Characteristics at Pain Onset. Biol Res Nurs 18:401-10
Wu, Junfang; Zhao, Zaorui; Kumar, Alok et al. (2016) Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury. J Neurotrauma 33:1919-1935
Faden, Alan I; Wu, Junfang; Stoica, Bogdan A et al. (2016) Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol 173:681-91
Starkweather, Angela R; Ramesh, Divya; Lyon, Debra E et al. (2016) Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared With Healthy No-Pain Controls. Clin J Pain 32:933-939
Liu, S; Sarkar, C; Dinizo, M et al. (2015) Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis 6:e1582
Wu, Junfang; Sabirzhanov, Boris; Stoica, Bogdan A et al. (2015) Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury. Cell Cycle 14:3698-712

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