Description of Research Expertise

Currently, there are up to 6.5 million people in the United States living with the devastating physical, cognitive, and economic costs of traumatic brain injury (TBI). A significant component of TBI morbidity and mortality is caused by axonal stretch injury, also known as diffuse axonal injury (DAI). In DAI there is widespread damage to the white matter, and severe cases are associated with high mortality and poor outcome in survivors. An important characteristic of axonal stretch injury is rapid loss of microtubules (within 15 minutes). In regions where microtubules do not recover, axonal swellings develop, which are sites of organelle accumulation due to impaired axonal transport. Within several hours, secondary axotomy begins to occur at the site of axonal swellings. This delay in irreversible pathology suggests a potential therapeutic window for neuroprotective interventions. Although the cause of persistent microtubule loss after axonal stretch is unknown, one potential mechanism is calpain-mediated proteolysis of microtubule components.

Calpains are a family of Ca2+-dependent cytosolic proteases involved in cytoskeletal remodeling, cell-cycle regulation, signal transduction, cell differentiation, embryonic development, vesicular trafficking, and apoptosis and necrosis. There are two ubiquitous isoforms, µ-calpain and m-calpain, which differ in the Ca2+ concentration required for activity. Calpain activity has been detected within 15 minutes of DAI in animal models. A causal role for pathologic calpain activity after axonal injury is supported by calpain inhibitor studies, which demonstrate an attenuated disruption of axonal transport. Mechanistic investigations, however, have been limited by the fact that all synthetic calpain inhibitors that are effective in vivo are likely to inhibit other proteases. The only completely specific inhibitor of calpains is the endogenous inhibitor, calpastatin, which does not cross cell membranes. Furthermore, there are currently no inhibitors specific to either of the two ubiquitous calpain isoforms.

The downstream consequences of early calpain activation after axonal stretch injury are poorly understood. We are interested in understanding the role of calpain in axonal injury by using a rat optic nerve stretch model that simulates the mechanics of DAI in humans.

Description of Clinical Expertise

mild traumatic brain injury