• Accomplishments
• Contact

• Research
• Spinal Cord Injury Projects
• Traumatic Brain Injury Projects
  • Assessment & Intervention for Mild TBI
  • Can Eye Movements Predict Persistent Problems in Paediatric Mild TBI?
  • Cognitive and Neural Substrates of Socially Maladaptive Behaviours in Adolescents with Traumatic Brain Injury
  • DECRA Trial (DECompressive CRAniectomy Trial)
  • Enhancing Neurogenesis Post -TBI
  • Fluid Resuscitation in TBI
  • Headstart: Multi-family Groups for Traumatic Brain Injury
  • Hypothermia in Childhood TBI (HiTBIC)
  • Improving the functional communication ability of adults with TBI
  • Long term consequences of childhood head injury - 15 year follow-up
  • Longitudinal Hippocampal Study
  • Measuring the Impact of TBI on People's Lives
  • Mobility Following Childhood TBI
  • New Treatments for Brain and Spinal Cord Injuries
  • Neural Basis of Communication Disorder in Children
  • Neurotrauma Tissue/Fluid Bank
  • Normoglycaemia in Intensive Care Traumatic Brain Injury Study (NICE-TBI)
  • Preventing Neuronal Cell Death Following Brain Trauma
  • Prevention and Treatment of Social Problems Following TBI
  • Rehabilitation of Attention Following TBI
  • Role of Tissue Type Plasminogen Activator
  • TBI in Older Adults
  • Transcranial Magnetic Stimulation (TMS) Treatment in Depression After Traumatic Brain Injury
  • Traumatic Hypoxia and Cerebral Inflammation
  • Virtual Reality and Upper Limb Function Following TBI in Children
• Targeted Initiatives
• Completed TBI and SCI Projects
• Program Grants

Role of Tissue Type Plasminogen Activator

To Determine the Role of Tissue Type Plasminogen Activator in Models of Traumatic Brain Injury

Chief Investigator: Dr Robert Medcalf
Associate Investigators: Associate Professor Cristina Morganti-Kossmann, Professor Harald Schmidt
Lead Organisation: Monash University
VNI Funding: $578,064
Project Start Date: 05-Apr-07

Project Summary:
Tissue-type plasminogen activator (t-PA) is a naturally occurring protease that is used clinically to remove blood clots in patients with myocardial infarction and under limited conditions in patients with ischaemic stroke. However, a large body of evidence has now demonstrated that t-PA has a role in the brain. Indeed, t-PA has been shown to have a beneficial role in memory development, synaptic plasticity and visual processing. Although these effects in the brain are beneficial, under pathological conditions, including traumatic brain injury (TBI), the presence of t-PA is detrimental.

This project aims to use an established mouse model to dissect the mechanisms by which t-PA exacerbates secondary damage following TBI. We have mice that express no t-PA (t-PA -/- mice), as well as a transgenic mouse that expresses 10-times higher levels of t-PA in the brain. By comparing the degree of injury following TBI in these mice, we will be able to correlate t-PA levels with outcome. We will also use these models to block endogenous t-PA using selective inhibitors to determine whether pharmacological intervention will be a viable approach to reduce severity of TBI and improve recovery.

To complement this we will also determine levels of t-PA in the cerebrospinal fluid (CSF) of TBI patients and determine if t-PA levels in CSF correlates with severity of TBI. Finally, we also propose that the damaging effect of t-PA may be related to its ability to activate the matrix metalloproteinase (MMP) pathway, as the activation of some MMP family members is regulated by plasmin generation and our preliminary data provide circumstantial evidence that suggests t-PA mediated activation of the MMP system following TBI. We are also interested in exploring the possible protective effects of the tyrosine kinase inhibitor, imatinib (Gleevec) which has recently been shown to be effective at attenuating the potentiating effect of t-PA mediated ischaemic damage following stroke.

Taken together we anticipate that this project will provide a mechanism based approach for novel treatments following TBI.