We have developed a new in vitro model of the glial scar in which inhibitory CS-PG in a crude gradient more closely resembles that which occurs in vivo after injury. Classic dystrophic endballs form at the tips of adult sensory axons that become trapped within the gradient. We can now ask, for the first time, a variety of basic questions concerning the biology of the dystrophic growth cone. Three important questions we wish to pursue in aim 1 are: (A) whether the dystrophic state is a peculiarity of adult neurons, (B) whether CNS neurons would respond similarly to the PG gradient environment and, (C) whether dendrites respond differently to the inhibitory gradient than do axons. Finally, (D) we would like to know what molecular changes occur in would- be dystrophic axons that are induced to regrow across the potently inhibitory rim of the gradient via a new combinatorial regeneration stimulating strategy. Our ultimate goal is to devise an optimal strategy in vitro that can be used to overcome growth cone dystrophy and stimulate axon regeneration past the glial scar in vivo.
In aim 2, preliminary in vivo results based on a successful regeneration promoting strategy using our in vitro gradient model, have shown evidence that a combination of chronic sterile inflammation induced in the DRG prior to root crush, plus chondroitinase application to the root entry zone at the time of crush, can foster robust regeneration of sensory axons into the spinal cord. We hypothesize that a similar strategy may foster sensory fiber regeneration in a more clinically relevant post-injury model. We propose to study the functional efficacy of these fibers.
In aim 3, we will utilize a novel microlesion model of the cingulum in which one can make the smallest lesion possible but still clearly identify only those axons that have been severed and have potentially regenerated. With the microlesion model, we can use the micropipette, that cuts the axons, to inject bridge building cells or other factors upon withdrawal of the pipette from the brain. Preliminary evidence shows that injection of chondroitinase combined with immature astroglia can stimulate regeneration clearly past the lesion. None-the-less, once past the lesion the fibers only grow short distances. Using this model we hypothesize that by also driving the intrinsic growth potential of the regenerating neurons at the vicinity of their cell body, regeneration will be significantly enhanced.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Cregg, Jared M; Chu, Kevin A; Dick, Thomas E et al. (2017) Phasic inhibition as a mechanism for generation of rapid respiratory rhythms. Proc Natl Acad Sci U S A 114:12815-12820
Cregg, Jared M; Chu, Kevin A; Hager, Lydia E et al. (2017) A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury. Cell Rep 21:654-665
Johnsen, Dustin; Olivas, Antoinette; Lang, Bradley et al. (2016) Disrupting protein tyrosine phosphatase ? does not prevent sympathetic axonal dieback following myocardial infarction. Exp Neurol 276:1-4
Filous, Angela R; Silver, Jerry (2016) ""Targeting astrocytes in CNS injury and disease: A translational research approach"". Prog Neurobiol 144:173-87
Filous, Angela R; Silver, Jerry (2016) Neurite Outgrowth Assay. Bio Protoc 6:
DePaul, Marc A; Lin, Ching-Yi; Silver, Jerry et al. (2015) Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice. PLoS One 10:e0139335
DePaul, Marc A; Palmer, Marc; Lang, Bradley T et al. (2015) Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury. Sci Rep 5:16795
Gardner, R T; Wang, L; Lang, B T et al. (2015) Targeting protein tyrosine phosphatase ? after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nat Commun 6:6235
Vadivelu, Sudhakar; Stewart, Todd J; Qu, Yun et al. (2015) NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury. Stem Cells Transl Med 4:401-11
Lang, Bradley T; Cregg, Jared M; DePaul, Marc A et al. (2015) Modulation of the proteoglycan receptor PTP? promotes recovery after spinal cord injury. Nature 518:404-8

Showing the most recent 10 out of 59 publications