Gunnersen Lab - Major Projects
Project 1 Molecular mechanisms of maladaptive plasticity in neuropathic pain
Supervisors: Dr Jenny Gunnersen and A-Prof Christine Wright, Dept. of Pharmacology
Neuropathic pain is a type of chronic pain caused by nerve damage. After traumatic peripheral nerve, spinal cord and brain injuries as well as diseases of the sensory nervous system, pain may persist for months or years after the original injury. In these cases, pain responses are amplified and even occur after stimuli that do not normally cause pain. In experimental pain models, it has been possible to measure changes in the structure and function (termed plasticity) of neurons that transmit sensory information to the brain. This “maladaptive plasticity” is now recognized as an important pathological mechanism contributing to neuropathic pain.
The drugs gabapentin and pregabalin are prescription medications that are effective against neuropathic pain. The receptor for these drugs is α2-δ, a component of calcium channels or “pores” in neurons. It is currently believed that gabapentin and pregabalin act on α2-δ to reduce the level of active channels at the cell surface and, hence, neuronal excitability. Sez-6 can enhance excitatory synaptic connections through binding to α2-δ. This project will examine the timing and levels of Sez6 expression in spinal cord neurons after sciatic nerve damage and relate these molecular changes to the development of neuropathic pain.
Project 2 Enhancing excitatory synapse formation through Sez-6 signalling
Supervisor: Dr Jenny Gunnersen
Although we recently discovered a role for Sez-6 in the development of excitatory synapses (Gunnersen et al., 2007, Neuron 56, 621-639), the molecular pathways mediating this effect are not known. Our recent investigations have focussed on identifying Sez-6 binding partners and interactions that can enhance excitatory synapse formation in a cultured neuron model. We are also investigating downstream signalling pathways (including calcium signalling) for their role in synaptogenesis. This project will investigate protein-protein interactions and signalling events in order to characterize a new synaptogenic signalling pathway.
Project 3 Wnt signalling in the development of neuronal connectivity
Dr Jenny Gunnersen and Dr Clare Parish, Florey Neuroscience Institutes
Activity of the Wnt patterning and differentiation factors is vital for nervous system development. Their importance for promoting neuronal connectivity has recently been highlighted by the recent finding that neurons derived from induced pluripotent stem cells (iPS) from schizophrenia patients show aberrant Wnt signalling and reduced connectivity (Brennand KJ et al., 2011, Nature 473, 221-225). This project will compare the activities of different Wnt proteins and Wnt signalling pathways for promoting axon growth and synaptogenesis.
Project 4 The role of TCF7L2 (TCF4) in regeneration after spinal cord injury
Dr Jenny Gunnersen and Dr Matthew Digby, Dept. of Zoology
The transcription factor TCF7L2 (also called TCF4) is a downstream effector of the canonical Wnt pathway that is important for cell fate/differentiation in development. TCF7L2 is strongly upregulated in response to spinal cord injury and is this upregulation is associated with the ability of the immature spinal cord to regenerate after injury (Mladinic M et al., 2010, Brain Res. 1363, 20-39). Interestingly, different forms of this transcription factor have different, even opposite effects. This project will investigate the different splice-isoforms of the messager RNA for TCF7L2 in the mouse spinal cord in injury models.
Project 5 What does GM-CSF do in the developing brain?
Dr Jenny Gunnersen
While granulocyte-macrophage colony stimulating factor (GM-CSF) is best known as a haematopoietic cytokine stimulating production of blood progenitor cells, this cytokine and its receptor are found in the brain. Recent evidence suggests that cytokines, including GM-CSF, can exert neuroprotective effects after stroke or in other neurodegenerative conditions. Our data shows that GM-CSF can promote the growth of cultured embryonic cortical neurons however the role of GM-CSF in the developing brain is not known. This project will use cultured neuron and mouse models to study this question.