Developing mimetic peptides to inhibit central nervous system inflammation

Project code:  MHS102

Department

  • Centre for Brain Research
  • Anatomy and Medical Imaging

Supervisor

Simon O’Carroll

Our laboratory has an interest in gap junction, connexin43 (Cx43), biology in pathology. Cx43 forms gap junctions between cells, which are involved in a number of important physiological processes. There is now extensive evidence that Cx43 is involved in a number of disease processes and we have shown that blocking connexin43 channels by using a mimetic peptide limits damage and spread of inflammation in several injury models such as spinal cord injury, retinal ischemia and fetal ischemia. It has recently been discovered the connexins can form singular unopposed ‘hemichannels’ that allow for communication between the cytoplasm and extracellular environment. There is increasing evidence that connexin hemichannels are the main contributor to connexin associated pathology as it has been shown that they may open in response to a variety of pathological stimuli. This opening of hemichannels is thought to contribute to loss of ionic gradients and membrane integrity, and spread of injury. Therefore blocking these Cx43 hemichannels is therapeutic.

An issue for the clinical translation however is that the half-life of the mimetic peptide in the blood in very short. Therefore, with collaborators in the School of Chemical Sciences, a large number of modified analogues of the parent peptide have been created in ways that aim to increase serum stability while maintaining biological activity. We have discovered that a number of these peptides have different efficacy against Cx43 gap junctions and hemichannels. This project will allow us to develop peptides that inhibit the pathological effects of Cx43 hemichannels while not interfering with the physiological roles of Cx43 gap junctions.

Skills

This project will use cell culture techniques such as ATP release, dye transfer and cell death assays, along with imaging and western blotting to determine which of the modified peptides is most specific for Cx43 hemichannels. This project will help us in developing a specific Cx43 hemichannel drug as a treatment for a number of devastating neurological disorders.