David P. Stirling, Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, USA

The role of axoplasmic reticulum in axonal degeneration following SCI

Funded in: 2014, 2015, 2016

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Problem: After initial damage, axons degenerate following spinal cord injury.

Target: Inhibiting intra‐axonal Ca2+ release mechanisms to protect axons following SCI.

Goal: Unveil novel therapeutic targets to prevent axon loss after SCI.

How axons degenerate following SCI is unclear, as well as the involvement of the axoplasmic reticulum (AR), an endomembrane system within axons that serves as intra-axonal calcium (Ca2+) store. Preliminary data from this group support an important role for elevated Ca2+ release in mediating axonal dieback and secondary degeneration of axons acutely after SCI. AR mediated pathologic Ca2+ induced Ca2+ release (CICR) causes secondary axonal degeneration. Therefore, inhibiting intra‐axonal CICR will protect axons following SCI.

The specific aims of the project are to,
1. Determine the role of the Ca2+ release mechanisms in secondary axonal injury following SCI, and
2. Evaluate the best clinically relevant approaches to interfere with these mechanisms.

The approach exploits live imaging of injury-induced axon and calcium dynamics. Using two‐photon excitation microscopy combined with an ultrafast resonant scanner the changes in the axons, myelin integrity, and in AR structure can be directly assessed.
The overall objective of this project is to protect central nerve fibers following SCI by targeting Ca2+ release channels.
The approach taken may also unveil potential novel therapeutic targets and clinically relevant treatments (e.g., carvedilol, FDA approved) to promote neurological recovery after SCI.