WAIMR - NRP Highlights

NRP's Research Highlights

NRP researchers are finding the answers to important questions regarding neurotrauma - shedding light on how brain and spinal cord tissue reacts when damaged and what is needed to ensure the survival and recovery of this delicate and complex central nervous system.

1. Cell survival during oxygen depletion; investigating the molecular mechanisms that might "nurse" nerve cells through periods of trauma

Dr Peta Tilbrook established (during the first two years of the NRP):
- a method of isolating and characterizing the genes induced when the hormone erythyopoietin (Epo) rescues nerve cells from oxygen starvation, which occurs during both traumatic head injury and stroke.
A/Professor Neville Knuckey and Dr Bruno Meloni have:
- confirmed that magnesium chloride, magnesium sulfate and sodium sulfate can each reduce tissue death following oxygen starvation in a confined area of the brain;
- demonstrated that applying a combination of magnesium sulfate and mild hypothermia for a specific time period following brain injury reduces neuronal death even more significantly;
- identified 55 proteins that represent potential therapeutic targets for the development of drugs to reduce brain cell death following brain injury.
Dr Peter Arthur's team has:
- demonstrated that human brain cells can adapt to reduced oxygen concentrations by "hibernating" (just like the turtles that inspired this work!);
- developed a reliable brain cell culture model that allows the examination of signaling pathways involved in delayed neuronal death;
- developed a 'peptide inhibitor' to block the activity of one of the key proteins responsible for delayed brain cell death following injury;
- discovered that this peptide inhibitor prevents necrotic cell death (often considered an irreversible process) as well as programmed/delayed cell death;
- discovered that the inhibitor may work by blocking production of reactive oxygen species (free radicals) from the mitochondria.

2. Studying human spinal cord injury

Professor Byron Kakulas has:
- observed the presence of Schwann cells after spinal cord injury, leading to an increased understanding of their role;
- demonstrated that a structure called Clarke's nucleus survives in spinal cord injury patients, providing an answer to a common question posed by experimental neurobiologists in recent times;
- almost completed a human spinal cord injury atlas, a much needed neuroscience resource as we fast approach human clinical trials in the development of new treatment techniques for spinal cord injury.

3. Central nervous system repair and regeneration

Professor Alan Harvey, Dr Giles Plant and Dr Qi Cui have:
- successfully transplanted mouse olfactory ensheathing glial (OEG) cells into the injured adult mouse spinal cord, observing strong nerve re-growth into, across and beyond the lesion sites, with good behavioural results;
- developed techniques to deliver DNA into OEG cells, enabling them to produce growth factors that act as 'fertilizers' for injured spinal cord axons (preparation for the transplantation of OEG cells from the human nose into the rat spinal cord and then ultimately for OEG cells to be taken from the nose of a patient with spinal cord injury to repair and regenerate the patient's own injured cord);
- developed allograft and reconstructed peripheral nerve graft models in rats for central nervous system repair (a revolutionary approach using donor nerve sheaths and the host's own Schwann cells, obviating the need to harvest the host's own major peripheral nerves, thus minimizing additional neurological deficits). These cells have now been genetically engineered so that they make additional growth-promoting factors;
- discovered ways of massively increasing survival and regeneration of adult retinal ganglion cells using gene therapy, and using growth factors in combination with analogues of cyclic AMP. Agents have also been successfully trialed that block growth-inhibitory molecules normally present in the adult brain and spinal cord;
- for the first time, examined whether it is possible to use stem cell-like cells to selectively replace mouse and rat retinal neurons that have died as a result of injury.
Dr Stuart Bunt and Professor Sarah Dunlop have:
- set up a state of the art live cell-imaging facility in 1999, that for the first time allowed scientists to visualise re-growing nerve fibres in living spinal cord tissue. Direct insights were gained into how nerve fibres can be appropriately guided by applying various agents to encourage and direct growth.
Professor Sarah Dunlop and Dr Giles Plant have:
- ascertained the ability of adult, postnatal and embryonic OEG cells to myelinate axons in culture.
Dr Samantha Busfield and Dr Joanne Britto have:
- identified a protein called DR6 that is capable of triggering delayed (programmed) cell death following damage to the nervous system - a major obstacle in the treatment of head and spinal injuries;
- revealed many molecules that may be involved in promoting axonal regeneration following injury (and are now being further investigated);
- confirmed that a molecule called NRG-2 has an effect on cultured stem cell proliferation and differentiation.
Dr Carolyn King and her team have:
- demonstrated that administration of a small metal-binding protein that occurs naturally in the human body is capable of inducing significant regeneration of injured nerve fibres in animal studies. The molecule was also found to offer extensive neuro-protection.

4. Re-establishing orderly projections in target tissue of the brain

Professor Lyn Beazley and Professor Sarah Dunlop have:
- determined that the fibres surviving a partial lesion of the optic nerve positively influence the ability of those that were damaged to find their correct destinations in the brain;
- demonstrated for the first time the expression of a key "map making" molecule, Ephrin A2, during optic nerve regeneration, vital for restoration of orderly connections in the brain after injury (collaborating with Professor Peter Klinken);
- made significant progress in understanding the activity of key map-making molecules (Eph/ephrins and Pax genes) and how these must interact to re-establish order and function in the brain following neurotrauma (collaborating with Associate Professor Dale Roberts, Dr Jenny Rodger and Dr Carolyn King);
- demonstrated that training during optic nerve regeneration converts an animal that would otherwise be blind into one that can see, confirming the importance of physiotherapy post injury (collaborating with Dr Jenny Rodger and Dr Carolyn King):
- In collaboration with Doctors Giles Plant, Marc Ruitenberg and Jenny Rodger, demonstrated :
  - that continued training is necessary for continued vision improvement
  - that visual training changes gene expression to allow nerve fibres to be guided to their correct locations and to function properly
  - a basis for being able to understand how rehabilitation works
  - the creation of a computerized gait analysis apparatus to qualitatively assess walking recovery in animals following neural injury and subsequent treatments and training
Professor Sarah Dunlop has over the last year:
- established a MAP network in WA, encompassing scientists in the Schools of Animal Biology, Human Movement and Exercise Science, Surgery and Pathology, Population Health and the Faculty of Medicine and Dentistry at UWA, physiotherapists at the Sir George Bedbrook Spinal Unit (RPH), and the Schools of Physiotherapy at Notre Dame University and Curtin University together with support groups such as Spinal Cure.

5. Neural re-organisation and recovery of function after brain injury