Watch A/Professor Kelli MacDonald accept the research grant award on behalf of Dr Jana Vukovic and hear a bit about the project.
Traumatic brain injury (TBI) is a leading cause of disability in Australia and worldwide. The effects of TBI are profound and often long term. Adverse outcomes are wide ranging and can include confusion, memory loss, depression, cognitive decline, epilepsy and eventual development of dementia. Unfortunately beneficial treatments are lacking due largely to our limited understanding of how TBI promotes these events.
TBI can be divided into two mechanistically distinct stages: the primary and secondary insult. The primary injury is the immediate and irreversible damage caused by mechanical forces during the accident. The damage caused by the primary insult is irreversible, however, the secondary injury is a driven largely by the ensuing inflammation that causes further cell death in the brain and adversely affects brain function. Importantly, early interventions to limit the inflammatory response following a significant brain impact represents a novel strategy to minimize secondary injury and improve outcomes.
We have found that the protein ROCK2 is rapidly increased in the brain following TBI. ROCK2 has an established role in driving pathogenic immune responses in multiple inflammatory diseases. In clinical studies, inhibitors of ROCK2 have been shown to limit inflammation to attenuate disease and reverse pathology in patients with psoriasis and pulmonary fibrosis. In the proposed study we will use our well established preclinical models to elucidate the mechanisms by which ROCK2 promotes injury following TBI, and test whether ROCK2 inhibition with a highly selective orally available small molecule inhibitor of ROCK2 (KD025) improves cognitive and behavioural outcomes.