Research interests - Dr. David Stirling
The consequence of spinal cord injury (SCI) is devastating with paralysis a common outcome. In addition to the immeasurable loss to the patient, the cost of SCI to society is huge, taking into account factors such as family impact, the lost productivity of the subject, and hospitalization and rehabilitation demands. Lessening the neurologic deficits that ensue from SCI, or promoting neural regeneration post-insult, are clearly highly desired outcomes.
It is recognized that immediately after SCI, there is primary injury that represents disruption of myelin and axons at the point and moment of impact. Over hours to weeks, however, the loss of myelin and axons (the CNS’s wiring that provides efficient transmission of signals and allows us to move and sense within our environment) continues and, indeed, becomes more extensive than the initial injury; this progressive atrophy is referred to as secondary degeneration and is contributed by mechanisms such as the production of free radicals, excitotoxicity and neuroinflammation. Reducing myelin and axonal degeneration after SCI has gained increasing prominence with the appreciation that sparing of as little as 5-10% of central myelinated fibers in the injured spinal cord is sufficient to support some locomotor function below the level of injury.
The inflammatory response that soon ensues after CNS injury is arguably one of the most controversial areas of SCI research as studies have provided both protective and detrimental effects from targeting key effector molecules and cells. Adding to this complexity is the lack of cell specific markers to distinguish between resident CNS macrophage populations (e.g. microglia) and blood-derived macrophages recruited to the injury site. Furthermore, as demonstrated in other models of inflammation, macrophages can become polarized to respond as pro- or anti-inflammatory cells. Thus anti-inflammatory treatments that globally target the macrophage response may be counterintuitive as they will likely hinder important spinal cord wound healing or repair processes mediated by subsets of these cells.
Microglia, key players in the immune response to CNS infection, injury, and disease, are the first responders to SCI and their activation precedes recruitment of blood-derived immune cells (neutrophils and monocytes). Their activation profile also correlates temporally and spatially with ongoing loss of central myelinated fibers. However, what remains to be determined is whether microglia activation and subsequent release of potential neurotoxic molecules, directly cause damage to myelin and axons or protect them after SCI. Although cell culture experiments clearly provide evidence to support a role for microglia in inducing axon/dendrite degeneration, very little is known about how these cells respond to SCI in living tissue. Indeed, the precise molecular cues that activate microglia, attract them to sites of injury, stimulate the release of potential toxic molecules or protective molecules are processes that are poorly understood.
To shed “light” on this complex interplay between neuroinflammation and secondary central myelinated fiber degeneration, we utilize advanced optical imaging systems such as two-photon spectral microscopy to differentiate, observe, quantify, and probe subpopulations of immune cells as they respond to SCI. This “intravital window” allows us to document immune cell interactions simultaneously with ongoing myelinated fiber degeneration as these dynamic processes are occurring in real time in the injured spinal cord setting. It is hoped that the information gathered from these basic science studies will unveil novel therapeutic targets to modulate the immune response following SCI and tip the balance from a destructive to a reparative response following human SCI.