Grants and Contracts Details
Description
Scientific abstract:
Macrophages inhibit axon regeneration and persist chronically within spinal cord lesions. The
goals of this project are to elucidate the role of chronically dwelling macrophages on
regenerative failure, as well as improve regenerative treatments by depleting macrophages in
chronic spinal cord injury (SCI).
Investigating chronic SCI is a top priority for individuals living with paralysis and therapeutic
investigations applicable to chronic SCI settings remain understudied. Axon regeneration has
been the focus of treatment efforts to restore lost function in severe cases of chronic SCI,
however regeneration in chronic SCI is limited compared to acute settings. Advances in
regenerative therapies for chronic SCI have demonstrated proof-of-principal that limited
regeneration is possible and can be enhanced through combinatorial approaches. Axons which
have been coerced to regenerate in chronic SCI avoid growing through the macrophage-rich
lesion core that persists chronically after injury. Instead, axons regrow through regions of
spared tissue or locations with astrocyte bridges spanning the lesion. Due to limited regions
capable of supporting axon regeneration, most fibers still do not successfully regenerate.
SCI lesion cores contain permanently elevated densities of macrophages and other inhibitory
fibrotic scar components. Acutely after SCI, macrophages collapse growth cones, lead to axon
dieback away from the lesion, and orchestrate cascades that result in the deposition of
extracellular matrix compounds that are inhibitory to axon growth. Indeed, infiltrating
macrophages have been determined to be a primary contributor to astrocyte and fibroblast
activation. However, the role of these macrophages on preventing regeneration in chronic SCI is
poorly understood. This project will determine the role of chronically dwelling macrophages
within the SCI lesion on inhibiting axons that are stimulated to regenerate chronically after
injury. We have optimized methods to deplete macrophages residing within the lesion core at
chronic SCI time points, as well as developed a novel gene delivery approach capable of
targeting all spinal-projecting neurons than have been damaged after injury.
Aim 1 of this work will utilize our macrophage depletion technique to investigate the role of
chronically dwelling macrophages after SCI on the maintenance of a growth-inhibitory
environment.
Aim 2 will determine the contribution of macrophages to regenerative failure in chronic SCI
settings by depleting macrophages from the SCI lesion using concurrent regenerative strategies
initiated chronically after injury.
Data collected from this project will determine the role of chronic neuroinflammation on
impedance of axon growth and repair and will develop an approach for future experiments
aimed at translating chronic regenerative treatments into real improvements for individuals
with spinal cord injury.
Status | Active |
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Effective start/end date | 7/1/22 → 6/30/24 |
Funding
- Wings for Life Spinal Cord Research Foundation: $132,000.00
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