Dissecting the Mechanistic Role of A Bioactive Small Molecule in Axon Regeneration as A Potential Therapeutic Target for Nervous System Injuries

Project: Research

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Description

The peripheral nervous system (PNS) regenerates successfully in contrast to the central nervous system (CNS) due largely to the enhanced intrinsic growth capacity that represents a major obstacle for successful axon regeneration in the CNS. In addition, proximal peripheral nerve injury (PNI) that requires long-distance axon regeneration and functional recovery becomes extremely limited due to slow rate of regenerating axons (1mm/day). Injuries to the PNS and CNS often results in permanent sensory and motor dysfunctions which greatly affect quality of life. The major challenge facing scientists and clinicians today is how to rekindle intrinsic growth capacity of injured neurons to achieve full functional recovery. Injury to the nervous systems induces either adaptive (growth and survival) or maladaptive (cell death and failure of regeneration) responses orchestrated precisely by a subset of genes. Key signaling pathways involved in the successful PNS axon regeneration are identified to be mostly inactivated after CNS injury, including JAK-STAT and mTOR signaling pathways. Co-deletion of Pten/Socs3 induced activation of both mTOR and JAK-STAT signaling pathways, which act synergistically to enhance robust axon regeneration in the CNS. Progress has been made in inducing genetic modification of neurons to facilitate axon regeneration. While the concept of gene therapy is straightforward, routine clinical implementation needs further development of efficient methods to deliver transgenes specifically to target tissues with high transduction efficiency. Therefore, there is an urgent need to identify bioactive small molecules as a ready-to-use therapy that could switch on the intrinsic growth capacity of injured neurons. To address this key question, we performed bioinformatic analysis for mining small molecule that associated with the regulatory networks of Pten/Socs3 co-deletion, and used the differentially expressed genes as gene expression signatures to query a public database of LINCS to match with over 1 million gene expression profiles derived from cell lines treated with 48,000 bioactive small molecules. We identified a clinical-relevant bioactive small molecule, SB-218795, which was first discovered as an antagonist for neurokinin-3 receptors. We demonstrated that SB-218795 increased significant in vitro and in vivo axon regeneration from axotomized PNS neurons, which accelerated functional recovery after PNI. More strikingly, SB-218795 induced robust and sustained CNS axon regeneration after optic nerve crush (ONC). In current proposal, we plan to optimize the therapeutic dosage regime for in vivo functional recovery after prolong muscle denervation (severe PNI) and CNS injury (ONC), and to elucidate the underling mechanism of SB-218795 in axon regeneration. 

Detail(s)

Project number9043117
Grant typeGRF
StatusNot started
Effective start/end date1/01/22 → …