Group Members
Senior Research Staff
- David W Walker (PhD, DSc)
- I Ross Young (PhD)
- Margie Castillo-Melendez (PhD)
- Edwin B Yan (PhD)
Research Staff
- Carly Woodd (BSc Hons)
- Isabella Ciurej (B Appl Sc)
Major Collaborators
- Jonathan Hirst (PhD) Mothers and Babies Research Centre
University of Newcastle. - Phuong Nguyen (PhD) National Trauma Research Institute
Alfred Hospital Campus, Monash University.
PhD Students
- Tamara Yawno (DW Walker, JJ Hirst)
- Hayley Dickinson (DW Walker)
- Bobbi Slattery (JJ Hirst, DW Walker, Vicki Clifton)
- Hannah Palliser (JJ Hirst, IR Young)
- Lisa Hutton (DW Walker)
- Poonam Ligam (DW Walker)
Honours Students
- Burcu Saglam (DW Walker, E B Yan JJ Hirst)
- Brooke Davies (IR Young, JJ Hirst)
- Zoe Ireland (DW Walker)
- Laura Olurich (DW Walker)
Current Research Focus
Contribution of disturbed blood flow and cerebral metabolism in white matter damage in the perinatal brain.
A significant number of newborn infants suffer from the effects of brain injury, despite recent improvements in obstetric care. Epidemiological studies suggest 80 to 90% of cases of cerebral palsy arise antenatally, rather than from intrapartum asphyxia. Regardless of whether the greater vulnerability is antepartum or intrapartum, perinatal brain injury represents a large source of potentially preventable neurological morbidity. A critical issue is the definition of the precise timing and causal mechanisms that produce this outcome. Asphyxia and infection are common threats faced by the fetus in utero. White matter injury, in particular, is thought to arise from inflammatory processes and oxidative stress particularly from the release of reactive oxygen species (ROS), prostaglandins (PGs), nitric oxide (NO), and other cytokine-mediated inflammatory reactions that occur predominantly in the reoxygenation and reperfusion phase following the insult. Cyclooxygenases, particularly COX-2 are induced by inflammatory conditions, and along with oxygen-starved mitochondria, comprise a major source of ROS in the brain during hypoxia and reperfusion. It is therefore clear that production of ROS and COX-2 expression are likely to interact and contribute to the expansion of cellular inflammatory responses leading to the loss of synaptic structure and function, breakdown of the BBB and brain cell death.
This project einvestigates the following proposals; that
- Fetal asphyxia results in loss of cerebral autoregulation, so that cerebral perfusion becomes pressure passive. When this actually happens in white and gray matter in relation to the asphyxial insult is currently not known.
- Asphyxia results in the production of reactive oxygen species - particularly the toxic hydroxyl radical (OH•). Precisely when this happens, and whether it is similar in white and gray matter, is also unknown.
- Asphyxia results in increased COX-2 expression in the cerebral vasculature of the fetal brain, and COX-2 dependent breakdown of the blood-brain barrier, resulting in the penetration of blood-borne protein and other substances into the brain.
The regulation of neurosteroid production in the fetus, and the role of steroids in fetal neural development and neuroprotection.
These studies aim to determine the level of steroid synthesis within the fetal brain and the possible function of placental steroids as precursors. The role of these steroids in preventing fetal brain injury resulting from stresses during pregnancy, and particularly during labour is also a major focus. The possible contribution of elevated sedative neurosteroid levels in the sudden infant death syndrome is currently under investigation. An important aspect of this work is the evaluation of a group of steroidogenic enzyme inhibitors, the 5[alpha]-reductase inhibitors, as a potential treatment for the prevention of SIDS and ALTEs.
Infection in pregnancy and its role in increased incidence of perinatal morbidity and brain damage.
In the fetus there is no clear understanding of the processes that lead to prenatal brain damage (eg, periventricular leukomalacia, intraventricular haemorrhage), or which manifest after birth as a brain dysfunction, behavioural deficits, or frank cerebal palsy.
We are currently examining:
The proposal that maternal infection (whether systemic or localised to intra-uterine sites), is associated with release of pro-inflammatory cytokines into the fetal circulation affecting fetal well being.
We are also investigating the recent finding that inflammatory stimuli (Eg Lipopolysaccharide treatment) increases the permeability of the blood brain barrier (which normally provides the brain with a stable and strictly controlled local environment to prevent substances in the circulation from entering the brain).This may allow neurotoxins (Eg Quinolinic acid) to enter the fetal brain, leading to brain injury.
The role of steroid hormones and prostaglandins in the initiation of normal and premature labour.
The main goal of this work is to determine the relative contribution of maternal and fetal prostaglandin synthase enzyme expression in the initiation of labour. These studies involve investigating the regulation of prostaglandin synthase enzymes in fetal and maternal tissues. We are currently examining new selective inhibitors of these enzymes for use in the treatment and prevention of preterm birth.
New methods for the detection and suppression of preterm birth.
The ability to manage the sequelae of preterm birth have improved over recent decades, but further improvements are unlikely until we have the means to:-
- inhibit myometrial activity, and
- identify impending preterm birth before uterine contractions are established.
The accomplishment of these objectives would represent a real breakthrough as it would permit the specific and timely treatment of affected women in tertiary care facilities. The novel treatments we will test can only be assessed in an animal model in which safety as well as potency can be determined.
Inhibition of myometrial activity: We and others have made considerable progress in recent years towards understanding the uterotonic mechanisms in women and sheep, and are now uniquely situated to exploit the knowledge gained in pursuit of the objectives above. Our studies indicate that, although the gestational tissues synthesize both of the uterotonic prostaglandins (PG) F2a and PGE2, only the synthesis of PGF2a is specifically increased at labour onset, and the myometrial expression of PG receptors does not change at this time. These new findings indicate that specific inhibition of PGF2a action is a desirable new component of tocolytic therapy. Indeed, we have shown that a novel PGF2a receptor (FP) antagonist markedly delays preterm labour. However, the mechanisms that control parturition do not form a linear, hierarchical control pathway. Rather, they represent a series of interlocking components that drive the dramatic increase in synthesis PGF2a at labour. Thus, any pharmacological intervention to be effective must curb PG synthesis as well as action.
We hypothesize that simultaneous inhibition of PG synthesis and blockade of the FP receptor will prove more efficacious than single drug therapies.
Thus, having defined a rational basis for a balanced tocolytic regimen, we now intend to test and refine the concept in pregnant sheep at the onset of physiologically induced labour. These studies are:-
- Examining new approaches for clinical trials and
- Further elucidating the biochemical mechanisms underlying the upregulation of PG production.
Detection of impending labour: The best available test for impending parturition (the fetal fibronectin test) does not reliably identify women who will proceed to preterm delivery. This test detects a component of the extracellular matrix at the feto-maternal interface which cannot be found in the vagina until the tissue at the interface has already started to break down, ie when the labour process is already established. What is needed is a biomarker that predicts and precedes the onset of labour. We have recently identified an antimicrobial protein of the cathelicidin family (bactenecin-1) as released into cervicovaginal fluid in advance of labour. Our findings suggest that antimicrobial proteins are released into the cervicovaginal fluid in preparation for labour before any rise in uterine activity. We will examine further antimicrobial proteins to determine if they can be used in combination with bactenecin-1 to maximize its positive predictive value.
We are currently;
- Characterizing the release of cathelicidins into the cervicovaginal fluid prior to labour, and
- Assessing the predictive value of other antimicrobial proteins (defensins) in detecting preterm labour.
Stress in Pregnancy, effects on the mother and fetus.
Psychological and physiological stress leads to activation of the hypothalamo-pituatry-adrenal (HPA) axis and increased secretion of glucocorticoids. It has been postulated that maternal stress results in maternal glucocorticoid secretion that passes to the fetus and generates negative effects (ie. Preterm labour, small-for-gestation babies, and increased posnatal morbitity).
The full acceptance of this idea is limited because it is known (at least in late pregnancy) that there are two highly effective protective mechanisms whose actions will tend to prevent the fetus from being exposed to excess maternal glucocorticoids. These are the placental 11b-hydroxysteroid dehydrogenase enzyme complex, that breaks down active cortisol to inactive cortisone, and the maternal HPA axis, that is resistant to reactivation. We are currently investigating the efficiency of the placenta in preventing the transport of active cortisol to the embryo and fetus in early, mid and late gestation, under situations of maternal stress and exposure to excess cortisol concentrations. In addition, the effect of these on the regulation of the fetal HPA in early, mid and late gestation is also being investigated.
Research Grants
| 2005-2007 NHMRC #34074 Contribution of disturbed blood flow and cerebral metabolism in white matter damage in the perinatal brain. Chief-Investigators D. W. Walker (A) J. J. Hirst (B) M Castillo-Melendez (C) A Walker (D) Awarded $122,500 per year for 3 years. |
2001-2005 NHMRC #143559 “The fetal response to infection, with particular reference to alterations of tryptophan metabolism” D. W. Walker (A), G. Smythe (B) |
| 2004-2006 NHMRC #284239 Neuroactive steroids in the developing brain: potential for preventing perinatal brain damage. J. J. Hirst Chief-Investigator (A) D. W. Walker (B) Awared $158,000 per year for 3 years. |
Major collaborative grant: 2003-2007 Canadian Institutes of Health Research. Application No. 93736 Prostaglandins F receptor and birth. Chief-Investigators D. M. Olson, B. F. Mitchell. All studies involving the sheep model of preterm labour will be performed in Australia by JJ Hirst IR Young. |
Figure 1. Increased allopregnanolone concentrations in the fetal sheep brain after occlusion of the umbilical cord for 10 min at time (0, indicated by vertical black bars). Concentrations were measured with microdialysis probes in a white matter region (A) and in a grey matter region (B). Does the increase in this suppressive neurosteroid protect the fetal brain from the effects of the hypoxic episode. *, indicates a significantly elevated allopregnanolone levels.
