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Journal article
Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury
Molecular therapy, Vol.25(12), pp.2715-2726
06 Dec 2017
PMCID: PMC5768590
PMID: 28967557
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration. We combined (1) transplantation of a growth-permissive peripheral nerve graft (PNG) into an incomplete, cervical lesion cavity; (2) transduction of neurons rostral to the SCI site to express constitutively active Rheb (caRheb; a Ras homolog enriched in brain), a GTPase that directly activates the growth-promoting pathway mammalian target of rapamycin (mTOR) via AAV-caRheb injection; and (3) digestion of growth-inhibitory chondroitin sulfate proteoglycans within the glial scar at the distal PNG interface using the bacterial enzyme chondroitinase ABC (ChABC). We found that expressing caRheb in neurons post SCI results in modestly yet significantly more axons regenerating across a ChABC-treated distal graft interface into caudal spinal cord than either treatment alone. Excitingly, we found that caRheb+ChABC treatment significantly potentiates the formation of synapses in the host spinal cord and improves the animals' ability to use the affected forelimb. Thus, this combination strategy enhances functional axonal regeneration following a cervical SCI.
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Details
- Title
- Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury
- Creators
- Di Wu - Drexel UniversityMichelle C. Klaw - Drexel UniversityTheresa Connors - Drexel UniversityNikolai Kholodilov - Columbia UniversityRobert E. Burke - Columbia UniversityMarie-Pascale Cote - Drexel UniversityVeronica J. Tom - Drexel University
- Publication Details
- Molecular therapy, Vol.25(12), pp.2715-2726
- Publisher
- Elsevier
- Number of pages
- 12
- Grant note
- R01 NS085426; P50 NS038370 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01NS085426 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991019167450104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental