Authors:*P. M. ABDUL-MUNEER, S. BHOWMICK, V. D’MELLO;
Hackensack Meridian Hlth. JFK Med. Ctr., Edison, NJ
Neuroscience 2019 LINK
Lab Abstract: Spinal cord injury (SCI) occurs when there is damage from trauma, loss of normal blood supply, or a mass effect due to compression from tumor or infection. Unlike other parts of the body, the regenerative ability of the spinal cord is relatively poor. The inability of axons to regenerate after SCI is attributable to a combination of effects of the non-permissive extrinsic factors including myelin proteins and chondroitin sulfate proteoglycans (CSPGs), and cell-autonomous intrinsic factors including cAMP, RhoA, Krüppel-like factors, mammalian target of rapamycin (mTOR) and phosphatase and tensin homolog (PTEN). However, the factor(s) that may be triggered to promote the initiation of a molecular growth program and axonal sprouting in SCI are largely unknown. In this project, we developed a novel therapeutic approach to treat SCI by exploiting the neuronal growth-promoting potential of growth differentiation factor 10 (GDF10), a potential gene belongs to the transforming growth factor beta (TGF-β) superfamily. GDF10 regulates several molecular signaling systems to induce a neuronal growth state. Our focus on GDF10 as a therapeutic target after SCI is based on the observation that GDF10 regulates major axonal regenerative cues including PTEN, phosphoinositide 3-kinase (PI3K) and suppressor of cytokine signaling 3 (SOCS3). Thus, we hypothesize that up-regulation of GDF10 mitigates PTEN-mediated inhibition of axonal regeneration. We examined the specific effects of GDF10 on other major regulatory signaling cascades of axonal regeneration, the PI3K, and SOCS3 pathways in vitro and in vivo. In order to up-regulate GDF10 in experimental animals, we delivered GDF10 gene via adeno-associated virus into the sensory-motor cortical area of the brain and into the spinal cord rostral to the SCI lesion, and evaluate the subsequent progress of axonal regeneration and functional recovery after SCI. To validate the role of GDF10 in axonal regeneration, we used the CRISPR/Cas9 gene deletion technology to remove GDF10 gene. Findings from this project would help to clarify the specific role of GDF10 in axonal regeneration and functional recovery after SCI and establish a basis for pursuing GDF10 as a therapeutic strategy for spinal cord injured patients.
NJ Commission on Spinal Cord Research Grant No. CSCR18ERG007
JFK Neuroscience Institute support package