After spinal cord injury (SCI) in adult mammals, progenitor cells and astrocytes within the spinal cord divide and migrate to the edge of the lesion site, where they undergo hypertrophy and alter their patterns of gene and protein expression. These responses contribute to formation of a dense glial border, which limits the expansion of inflammatory damage, but also creates a barrier to axonal growth and regeneration. The long term goal of this research program is understand the underlying mechanisms of glial scar formation and identify ways to modify this cellular response in order to improve the prospect of spinal cord repair. The central hypothesis is that spinal cord progenitor cells and astrocytes present in the adult spinal cord are dynamic cells that respond to local cues to change their behavior. Thus, in the presence of an appropriate stimulus, these cells can recruited as active participants for repair and can be stimulated to support growing axons after injury. Prior studies have shown that transforming growth factor alpha (TGFa) can stimulate the proliferation and migration of progenitor cells and astrocytes, and transform astrocytes to a growth supportive phenotype. The objective of this proposal is to determine if targeted activation of the epidermal growth factor receptor with TGF1 will enhance gliogenesis, neuroprotection, and astrocyte migration, and to establish if these responses can be exploited to induce the formation of permissive cellular bridges that will support axonal growth following SCI. The studies in Aim 1 will use loss of function and gain of function approaches to test the hypothesis that EGFR activation facilitates gliogenesis and enhances neuroprotection after SCI.
In Aim 2, EGFR activation will be combined with regenerative approaches to test the hypothesis that TGF1overexpression can facilitate the formation of growth supportive glial bridges after SCI. Finally, Aim 3 will employ in vitro and in vivo studies to determine if the effects of TGF1 are modulated by changes in inflammation in acute and chronic SCI. Completion of these aims will define the roles of EGFR activation in glial plasticity and neural repair after injury. These results will provide essential information about the function of cells surrounding the lesion site and serve as an important part of future combination strategies to reduce tissue loss and support axonal growth after SCI.

Public Health Relevance

As many as 1.4 million Americans have some form of paralysis due to injuries sustained in motor vehicle accidents, falls or violence. This research project will determine if cells present in the injured spinal cord can be stimulated to repair the site of injury. Information gained from these studies will contribute to new therapies that will improve recovery, reduce health care costs and allow a better quality of life for spinal cord injured persons in the US and throughout the world.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043246-09
Application #
8686967
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Lavaute, Timothy M
Project Start
2002-04-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Church, Jamie S; Milich, Lindsay M; Lerch, Jessica K et al. (2017) E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord. Glia 65:883-899
Goldstein, Evan Z; Church, Jamie S; Pukos, Nicole et al. (2017) Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage. Exp Neurol 298:42-56
Ma, Baofeng; Buckalew, Richard; Du, Yixing et al. (2016) Gap junction coupling confers isopotentiality on astrocyte syncytium. Glia 64:214-26
Kigerl, Kristina A; de Rivero Vaccari, Juan Pablo; Dietrich, W Dalton et al. (2014) Pattern recognition receptors and central nervous system repair. Exp Neurol 258:5-16
Jakeman, Lyn B; Williams, Kent E; Brautigam, Bryan (2014) In the presence of danger: The extracellular matrix defensive response to central nervous system injury. Neural Regen Res 9:377-384
Andrews, Ellen M; Richards, Rebekah J; Yin, Feng Q et al. (2012) Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. Exp Neurol 235:174-87
Jakeman, Lyn B; Hoschouer, Emily L; Basso, D Michele (2011) Injured mice at the gym: review, results and considerations for combining chondroitinase and locomotor exercise to enhance recovery after spinal cord injury. Brain Res Bull 84:317-26
White, Robin E; Rao, Meghan; Gensel, John C et al. (2011) Transforming growth factor ýý transforms astrocytes to a growth-supportive phenotype after spinal cord injury. J Neurosci 31:15173-87
Naphade, Swati B; Kigerl, Kristina A; Jakeman, Lyn B et al. (2010) Progranulin expression is upregulated after spinal contusion in mice. Acta Neuropathol 119:123-33

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