Featured Projects

 

TNF Sensori Motor Physiology and Therapeutics  

 

Industry Partnership for Development of Drug to Reduce Brain Injury in Stroke and Trauma

Project members

Scientia Professor Gary Housley

Professor

T:  +61 2 9385 1057

E:  g.housley@unsw.edu.au

 

Mr James Bonnar

CEO, Norbio No. 1 Pty Ltd

 

Project description

In stroke and traumatic brain injury (TBI), ischemia leads to rapid cell death and a prodigious expansion of the injury develops in the days following (the potential treatment window). The expansion of the brain injury is a large factor in the death and morbidity linked to stroke and TBI. Current treatments do not address this secondary wave of cell death. Original research out of the TNF showed that this secondary wave of death signalling in brain cells (neurons and glia) arises in large measure from entry of calcium ions (Ca2+) through ion channels coupled to G protein-coupled receptors (GPCR) that are tonically activated by dysregulated release of neurochemicals stemming from the initial brain injury (Kim et al.  J. Neurosci. 2012; Housley et al. 2018 Au Patent No. 2013286815). The opportunity to target this mechanism to treat brain injury was seized, via collaboration with the Australian biotech company Norbio No 1 (Nyrada Inc.  www.nyrada.com). Using a novel in vitro cell-based Ca2+ reporter assay developed in the TNF, a drug screen identified a promising stem compound that inhibited this GPCR-coupled Ca2+ entry brain injury mechanism. Current research at the TNF is providing critical evaluation of Norbio’s lead compound development, extending this to evaluation of neuroprotection in a preclinical stroke model (Nagarajesh et al. Translational Stroke Research 2018).  The collaborative research reflects significant progress towards an effective treatment for brain injury, that suppresses toxic calcium ion loading in brain cells following stroke and trauma, improving survivability and functional recovery. Norbio is seeking to advance the drug development through optimization steps so that it is poised for an Australia-based phase I clinical trial.

 

 

BIONIC ARRAY-BASED GENE ELECTROTRANSFER (BADGE®)

 

Project members

 

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  
g.housley@unsw.edu.au

 

Project supporters

Australian Research Council - Linkage Project|LP0992098

Project description

BaDGE® gene augmentation to improve the ‘Bionic Ear’: We are working to improve hearing and speech outcomes for cochlear implant recipients. Underpinning the BaDGE® gene augmentation platform technology which is migrating to a first-in-human clinical trial to regenerate the cochlear nerve and ‘close the neural gap’ with cochlear implants.    This work is supported by the CINGT program and includes co-investigators from the UNSW Biomedical Engineering Institute, the Bionics Institute (U. Melbourne), Dept. Otolaryngology U. Sydney, Sydney Cochlear Implant Centre, Macquarie University Hearing Hub and industry partner Cochlear Ltd.

 

 

HEARING PROTECTION CONFERRED BY P2X2 RECEPTOR SIGNALING IN THE COCHLEA

 

Project members

 

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  
g.housley@unsw.edu.au

 

Project supporters

National Health & Medical Research Council - Project Grant|APP630618

 

PHYSIOLOGICAL SIGNIFICANCE OF TRANSIENT RECEPTOR POTENTIAL (TRPC3) ION CHANNELS IN THE COCHLEA

Project members

 

Scientia Professor Gary Housley
Professor
T:  +61 2 9385 1057
E:  
g.housley@unsw.edu.au

 

Project supporters

Australian Research Council - Discovery Project|DP1097202

Project description

The transient receptor potential (TRPC3) ion channels provide Na+ and Ca2+ entry and are expressed in the cochlear hair cells and spiral ganglion neurons. A TRPC3 knockout mouse model will be used to test our hypotheses: (1) That loss of TRPC3 channel expression affects hearing function. (2) That TPC channels contribute to synaptic remodelling arising from noise exposure. (3) That TRPC3 Ca2+ entry channels contribute to cochlear hair cell Ca2+ homeostasis and regulation of membrane excitability. (4) That expression of TRPC3 channels by the spiral ganglion neurons is coupled to metabotropic glutamate receptor (mGluR) signaling and affects auditory nerve firing. (5) TRPC3 expression affects cochlear neural development.

 

 

TNF CNS Gene Therapy

We are generally interested in the molecular mechanisms of normal and pathological function of neurons and myelin forming cells in the central nervous system. Our aim is to establish gene therapy protocols for neurological disorders.

The success of our research relies on the availability of accurate animal models that we create by conventional transgenics or virus-mediated gene transfer. We have a long-standing interest in adeno-associated virus (AAV) as gene therapy vectors or as tools in basic research.

We are developing the current AAV platform in two directions:

(i) to achieve conditional transduction of specific neuronal sub-populations; and
(ii) to overcome the inherent neurotropism for targeting glia.

Using state-of-the-art techniques we employ a metabolomics approach, neuropharmacology, genetics, molecular biology and histology for our preclinical investigations on processes involved in memory formation and emotional behaviour but also severe conditions such as white matter disorders.

Projects related to this group

MODELING NEUROLOGICAL DISORDERS THROUGH VIRUS VECTOR-MEDIATED DYSREGULATION OF THE BRAIN METABOLITE N-ACETYL ASPARTATE

Project members

Adjunct Professor Matthias Klugmann

Adjunct Associate Professor

T:  +61 2 9385 1056
E:  
m.klugmann@unsw.edu.au

 

Scientia Professor Gary Housley
Professor

T:  +61 2 9385 1057
E:  
g.housley@unsw.edu.au

 

Project collaborators – external

Georg von Jonquieres

Postdoctoral Fellow

 

Project supporters

NSW Office for Science and Medical Research - NSW Life Sciences Research Award

Project description

CNS Gene therapy

 

TNF Neuropathic Pain Research

The principal aim of our research is to understand the relationship between the nervous system and the immune system, with particular emphasis on how immune cells and their mediators affect neuropathic pain, and to assess immunotherapeutic approaches. This knowledge can then be used for identifying target molecules or cells for therapeutic purposes in reducing chronic pain.

We use in vitro and in vivo models of neuropathic pain to investigate the neuroimmune crosstalk in the  injured nervous system. Animal models include peripheral nerve injury, chemotherapy-induced peripheral neuropathy, and an autoimmune disease of the central nervous system (experimental autoimmune encephalomyelitis, EAE; a model of multiple sclerosis). In vitro models include primary cultures of dorsal root ganglia sensory neurons, microglia and regulatory T cells. 

 

Projects related to this group

TARGETS AND MECHANISMS IN REDUCING NEUROPATHIC PAIN THROUGH IMMUNOMODULATORY TREATMENTS

Project members

Dr Gila Moalem-Taylor
Senior Lecturer

T:  +61 2 9385 2478
E:  
gila@unsw.edu.au

 

Project supporters

National Health & Medical Research Council - Project Grant| APP1162060

Project description

Inflammation in the central nervous system has been implicated in neuropathic pain, a debilitating chronic condition that imposes a huge economic and social burden. This project will investigate the effects of immunotherapeutic approaches, using spinal delivery of regulatory T cells and their novel anti-inflammatory mediator interleukin-35, on the molecular signature of CNS immune cells (microglia) and on the profile of immune responses in CNS boundaries using pre-clinical models of neuropathic pain due to nervous system injury or disease.

INVESTIGATING NEUROPROTECTIVE STRATEGIES IN CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

 

Project members

 

Dr Gila Moalem-Taylor
Senior Lecturer

T:  +61 2 9385 2478
E:  
gila@unsw.edu.au

 

Project supporters

Cancer Institute of NSW - CINSW 14/TPG/1-05 grant

Project description

At present, there are no effective treatments for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) and its progression. Thus, identifying neuroprotective strategies is a key priority for maintaining chemotherapy treatments and preventing neurological toxicities. Our research team has developed both in vitro and in vivo pre-clinical models of CIPN, which enable testing the effects of neuroprotective candidates on chemotherapy-induced neurotoxicity. These models include cultured dissociated sensory neurons isolated from dorsal root ganglia (DRG) of mice, and whole DRG explants (3D culture) with preserved microenvironment and intact cellular network. Treatment with the chemotherapeutic drugs oxaliplatin, a platinum-based intercalating agent, or paclitaxel, an anti-tubulin drug causes neurotoxicity, which is manifested by inhibition of neurite outgrowth and increased neuronal excitability. For in vivo studies, we developed physiologically relevant mouse models of oxaliplatin- and paclitaxel-induced peripheral neuropathy demonstrating quantifiable behavioural deficits, neuropathic pain symptoms, and nervous system damage. These models enable us to comprehensively assess the effects of novel compounds and identify the underlying mechanisms of their potential neuroprotective effects for the treatment of CIPN.

IMMUNOMODULATION OF NEUROPATHIC PAIN IN MULTIPLE SCLEROSIS

Project members

 

Dr Gila Moalem-Taylor
Senior Lecturer

T:  +61 2 9385 2478
E:  
gila@unsw.edu.au

 

Project description

The aims of this research are to assess the effects of immune modulation by inducing immune tolerance and manipulating regulatory T cells on pain behaviours in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This study promises to significantly enhance our understanding of the immunological mechanisms underlying neuropathic pain in MS and thereby offers hope for new approaches to therapeutic intervention.

 

 

 

TNF Neuro-systems

One aspect of the research conducted in the Neurosystems Group is to use viral-mediated gene therapy to modulate the levels of neurotrophins and other therapeutic molecules into the injured spinal cord with the aim of promoting axonal regeneration and the recovery of motor function.  An emerging theme within the Neurosystems Group is to characterise the effects of such deafferentation on these motor neurons. Methods of investigation include immunohistochemistry, western blotting and ELISA, RT-PCR and nerve excitability techniques. Another facet of the research in the Neurosystems Group is to investigate the neural basis of skilled reaching. Rats are trained to reach for sugar pellets, a paradigm called the "Single Pellet Skilled Reaching Task" after which they are subjected to different lesions of the brain and spinal cord that are known to be involved in motor control. The main objective is to characterise the exact contribution of these structures to fine motor control of the forelimb and the paw.

Projects related to this group

 

MODULATION OF BDNF EXPRESSION IN MOTOR NEURONS TO PROMOTE RECOVERY OF HAND/DIGITS MOTOR FUNCTIONS IN A RAT MODEL OF RUBROSPINAL TRACT INJURY

 

Project members

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  
renee.morris@unsw.edu.au

 

Project supporters

Christopher and Dana Reeve Foundation (USA) - Individual Research Grant

DELIVERY OF BDNF TO MOTOR NEURONS TO PROMOTE AXONAL REGENERATION AND RECOVERY OF MOTOR FUNCTION

 

Project members

 

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  
renee.morris@unsw.edu.au

 

Adjunct Professor Matthias Klugmann
Adjunct Associate Professor

T:  +61 2 9385 1056
E:  
m.klugmann@unsw.edu.au

 

Project supporters

Brain Foundation - Research Grant

Project contacts

Dr Renee Morris
Senior Lecturer

T:  +61 2 9385 8867
E:  
renee.morris@unsw.edu.au

 

 

 

TNF Augmented Sensorimotor Systems

The focus of our research is to “close the loop” on sensorimotor control. We use a combination of electrophysiology, signal processing and machine learning in small animal models to discover how sensory information is coded in different parts of the central nervous system. We are looking at certain brain regions for the potential to replaced lost sensory information with electrical inputs from a prosthetic device (neuroprosthesis).

Projects related to this group

Bionic touch

We are investigating the potential for the DCN as a somatosensory neuroprosthetic target. This project decodes sensory signals in the DCN in response to peripheral stimuli to predict the location and quality of sensory input. We will also stimulate the DCN to “recreate” the same electrical signatures evoked by natural stimuli.

DCN activity mapping

DCN activity is not symmetrically mapped across the surface of the brainstem. This project investigates the asymmetry of sensory representation in the context of handedness.

Spinal cord pre-processing of somatosensation

Sensory information may be significantly modified between the periphery and the DCN. This project focuses on the influence the spinal cord has on modulating ascending sensory inputs to the DCN.

Red light therapy in neuronal injury

Another interest of our group is how the somatosensory and motor systems are affected by injury. This project investigates the use of red-light therapy for treating the nervous system in response to injury.

 

Pain and touch processing  

How can we manipulate the brain and spinal cord to turn down unwanted pain, but without affecting touch and proprioception? We apply several approaches, which include the use of new nanomedicines and sophisticated electrical neuromodulation techniques to isolate pain pathways from other important somatosensory modalities.

 

Project contacts

Dr Jason Potas
Senior Lecturer

T:  02 9385 0017

E:  j.potas@unsw.edu.au

 

 

TNF NEUROPLASTICITY IN MEMORY & ADDICTION GROUP

Our group investigates the cellular mechanisms of memory formation. We aim to identify novel mechanisms that modulate or preserve neuronal connections. This may be translated into treatments for disorders of impaired or aberrant connectivity, such as addiction, Alzheimer’s disease, stroke, PTSD, and epilepsy.

Projects related to this group

Addiction associated neural plasticity

Drugs of abuse cause superphysiological activation of brain pathways involved in processing natural and drug rewards, overwhelming the homeostatic mechanisms that normally constrain reward-associated behaviours and neuronal plasticity.

 

The role of endoplasmic reticulum in neuronal calcium signaling

Memory and plasticity are governed by Ca2+. The endoplasmic reticulum (ER) is the primary regulatory organelle for Ca2+signalling. We have shown that metabotropic receptor stimulation releases Ca2+ from the ER generating wave-like rises in dendritic calcium that invade the nucleus and a subset of spines. Using genetically encoded Ca2+ sensors to we are evaluating the ER’s capacity to integrate Ca2+over space and time.

 

 

Project Contacts

Dr John Power
Senior Lecturer

T:  +61 2 9385 2910

E:  john.power@unsw.edu.au