According to the Christopher and Dana Reeve Foundation there are more than 1 million people with spinal cord injury (SCI) in the US. Developing strategies to promote regeneration and functional recovery after SCI has been a long and challenging goal. Although our lab was the first to recognize the critical role of sulfated proteoglycans in regeneration failure, the mechanisms by which the cells that produce this family of inhibitory extracellular matrix molecules block regeneration is largely unknown. Regenerating, albeit dystrophic, axons continually and tightly associate with a cohort of precursor cells in the core of the lesion that produce what is thought to be a potently inhibitory proteoglycan called NG2. The role of these NG2 cells and what has been purported to be a major proteoglycan in regeneration failure has become highly controversial. Our proposed studies will reveal for the first time how such highly preferred growth upon the surface of these cells results in an adhesive entrapment phenomenon that is likely to be a critical determinant in regeneration failure. Our proposed studies will also build upon the exciting discovery of a family of receptors on neurons that mediate, we propose via overly strong adhesive mechanisms, the inhibitory actions of CSPGs. Understanding in depth the complicated cellular and molecular interactions that lead to long term entrapment of axons within the glial scar will allow us to devise improved techniques for blocking or overcoming these untoward interactions and help in the search for strategies to stimulate robust regeneration beyond the glial scar.)

Public Health Relevance

The glial scar that develops after many forms of CNS trauma is a major obstacle to axon regeneration and functional recovery because of the production by certain reactive glial cells in the vicinity of the lesion of a family of potently inhibitory extracellular matrix molecules known as the chondroitin sulfate proteoglycans (CSPGs). Our exciting discovery with the John Flanagan lab of the first known receptors on neurons that mediate the inhibitory effects of these molecules has opened the door to the production of specific blocking peptides and knockout mice that can be used to test the effect of genetic ablation or pharmacological manipulation of these receptors on axon regeneration. Our exciting preliminary data also suggest for the first time how one critical CSPG, produced by a particular population of precursor cells in the lesion core, the NG2 glia, actually function to block regeneration by creating a state of dystrophy and entrapment of the would-be regenerating axon. Our proposed studies will shed light not only on the fundamental mechanisms of regeneration failure but also test new and potentially therapeutic strategies to foster regeneration after spinal cord injury.)

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025713-27
Application #
8606513
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
1988-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
27
Fiscal Year
2014
Total Cost
$309,094
Indirect Cost
$112,219
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Evans, Teresa A; Barkauskas, Deborah S; Myers, Jay T et al. (2014) High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp Neurol 254:109-20
Cregg, Jared M; DePaul, Marc A; Filous, Angela R et al. (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197-207
Silver, Daniel J; Silver, Jerry (2014) Contributions of chondroitin sulfate proteoglycans to neurodevelopment, injury, and cancer. Curr Opin Neurobiol 27:171-8
Barkauskas, Deborah S; Evans, Teresa A; Myers, Jay et al. (2013) Extravascular CX3CR1+ cells extend intravascular dendritic processes into intact central nervous system vessel lumen. Microsc Microanal 19:778-90
Lee, Yu-Shang; Lin, Ching-Yi; Jiang, Hai-Hong et al. (2013) Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J Neurosci 33:10591-606
Lin, Ching-Yi; Lee, Yu-Shang; Lin, Vernon W et al. (2012) Fibronectin inhibits chronic pain development after spinal cord injury. J Neurotrauma 29:589-99
Hawthorne, Alicia L; Hu, Hongmei; Kundu, Bornali et al. (2011) The unusual response of serotonergic neurons after CNS Injury: lack of axonal dieback and enhanced sprouting within the inhibitory environment of the glial scar. J Neurosci 31:5605-16
Busch, Sarah A; Hamilton, Jason A; Horn, Kevin P et al. (2011) Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury. J Neurosci 31:944-53
Alilain, Warren J; Horn, Kevin P; Hu, Hongmei et al. (2011) Functional regeneration of respiratory pathways after spinal cord injury. Nature 475:196-200

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