Peripheral Mechanisms & Injury Laboratory
Head of laboratory
On this page:
- Overview of research program
- Major funding sources
- Selected publications
- Major collaborations
- Research project opportunities
Overview of research program
We are interested in the development of nerve circuits, and how adult neurons are affected by injury and inflammation. Most of our studies focus on peripheral nerves and the spinal cord, especially the pain-sensing neurons (nociceptors) and motor neurons controlling the urogenital organs (reproductive organs and lower urinary tract). We are especially interested in how neurotrophic factors and gonadal steroids (estrogens and androgens) affect pain and pelvic autonomic function.
One major goal is to understand the mechanisms underlying pelvic visceral pain (e.g. bladder pain, interstitial cystitis) and spinal cord injury pain (chronic neuropathic pain) so that better treatments can be developed. We are also investigating how pelvic autonomic neurons can regrow after injury, so that we can develop therapies to promote regeneration. The axons of these neurons are often injured during pelvic surgery such as prostatectomy, hysterectomy and lower bowel resections, and this leads to continence problems and erectile dysfunction. Our studies on developing neurons may provide us with clues about how their axons reach their target organs early in life, and may reveal mechanisms that can be used to stimulate growth and guide the injured axons to their correct locations after injury later in life.
To address these questions we use a variety of experimental approaches, including neuroanatomy, microsurgery, tract tracing, immunohistochemistry, image analysis, neuronal cultures, cell and molecular biology, organ bath pharmacology and behavioural testing.
Recent research outcomes include:
- First detailed anatomical mapping of how spinal cord injury affects five different populations of pain-related nerve fibres in the spinal cord, showing changes that may relate to onset or maintenance of neuropathic pain.
- Discovery that erectile dysfunction occurring after peripheral nerve injury is caused mainly by adaptive changes in properties of the vascular muscle rather than aberrant or defective nerve regeneration.
- Identification of estrogen receptors and estrogenic growth responses in male pelvic autonomic neurons, suggesting new mechanisms for potentially modulating regeneration after injury.
- Demonstration of a remarkable degree of androgen-driven plasticity in adult male pelvic autonomic neurons, which controls how well the nerves communicate with reproductive smooth muscle.
- Discovery of a novel inhibitory effect of estradiol on the capsaicin receptor, TRPV1, in nociceptor neurons.
Major funding sources
- National Health and Medical Research Council
- National Institutes of Health (US)
- NSW Office of Science and Medical Research (Spinal Cord Injury and Related Neurological Conditions Program)
- Australian and New Zealand College of Anaesthetists
Selected publications
Nangle MR, Keast JR. Deafferentation and axotomy each cause neurturin-independent upregulation of c-un in rodent pelvic ganglia. ]]Experimental Neurology. 2008 (in press).
Xu S, Cheng Y, Keast JR, Osborne PB. 17beta-Estradiol activates ER-beta signalling and inhibits TRPV1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology 2008 149:5540-5548.
Yan H, Keast JR. Neurturin regulates postnatal differentiation of parasympathetic pelvic ganglion neurons, initial axonal projections and maintenance of terminal fields in male urogenital organs. Journal of Comparative Neurology. 2008 507:1169-1183.
Forrest SL, Keast JR. Expression of receptors for glial cell line-derived neurotrophic factor family ligands in sacral spinal cord reveals separate targets of pelvic afferent fibers. Journal of Comparative Neurology. 2008 506:989-1002.
Nangle MR, Keast JR. Reduced efficacy of nitrergic neurotransmission exacerbates erectile dysfunction after penile nerve injury despite axonal regeneration. Experimental Neurology. 2007 207:30-41.
Purves-Tyson TD, Arshi MS, Cheng Y Handelsman DJ, Keast JR. Androgen and estrogen receptor mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia. Neuroscience. 2007 148:92-104.
Kalous A, Osborne PB, Keast JR. Acute and chronic changes in dorsal horn innervation by primary afferents and descending supraspinal pathways after spinal cord injury. Journal of Comparative Neurology. 2007 504:238-253.
Brock JA, Handelsman DJ, Keast JR. Postnatal androgen deprivation dissociates the development of smooth muscle innervation from functional neurotransmission in mouse vas deferens. Journal of Physiology. 2007 581:665-678.
Wanigasekara Y, Keast JR. Nerve growth factor, glial cell line-derived neurotrophic factor and neurturin prevent semaphorin 3A-mediated growth cone collapse in adult sensory neurons. Neuroscience. 2006 142:369-379.
Llewellyn-Smith IJ, DiCarlo SE, Collins HL, Keast JR. Enkephalin-immunoreactive interneurons extensively innervate sympathetic preganglionic neurons regulating the pelvic viscera. Journal of Comparative Neurology. 2005 488:278-289.
Major collaborations
- A/Prof James Brock, Prince of Wales Medical Research Institute
- Prof David Handelsman and Dr Ulla Simanainen, Anzac Institute
- A/Prof Ida Llewellyn-Smith, Flinders University
Research project opportunities
Supervised by Associate Professor Janet Keast
