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Network Member Profile

Current Field of Study

Perturbations of the environment in early life, including both the prenatal and postnatal environments, alter growth and functional development and have a major impact on life long health and disease risk. Our laboratory has made novel and significant contributions to understanding the importance of both prenatal placental and postnatal lactational environments in the programming of perinatal growth restriction and catch up growth following placental restriction. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. We are the first to demonstrate that placental compromise in rats also adversely affects breast development, milk quality and supply, which further impair growth during lactation. This is followed by accelerated growth after weaning, programming more adverse outcomes. The consequences of the perinatal growth restriction on adult hypertension, diabetes and obesity are also being explored.

Defining the underlying mechanisms responsible will provide insight into early life interventions that may lessen these adverse consequences for longer-term health. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health in this emerging field.

Keywords: Fetus, newborn, programming, adult disease, diabetes, hypertension, Growth & development

Australian Collaborators

• A/Prof Jane Moseley (Department of Medicine, University of Melbourne, Melbourne, VIC)
• Prof Julie Owens (Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA)
• A/Prof Greg Cooney (Garvan Institute of Medical Research, Sydney, NSW)
• A/Prof Greg Rice (Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne, VIC)
• Dr Kevin Nicholas (Department of Zoology, University of Melbourne, Melbourne, VIC)
• Dr Laura Parry (Department of Zoology, University of Melbourne, Melbourne, VIC)
• A/Prof Helena Parkington (Department of Physiology, Monash University, Melbourne, VIC)
• Dr Marianne Tare (Department of Physiology, Monash University, Melbourne, VIC)
• Dr Karen Moritz (Department of Anatomy & Cell Biology, Monash University, Melbourne, VIC)
• A/Prof Margaret Morris (Department of Pharmacology, University of Melbourne, Melbourne, VIC)
• Dr Darryl Russell (Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA)
• Prof John Wark (Department of Medicine, University of Melbourne, Melbourne, VIC)
• Dr Damien Myers (Department of Physiology, University of Melbourne, Melbourne, VIC)
• Dr Glenn McConell (Department of Physiology, University of Melbourne, Melbourne, VIC)
  

International Collaborators

• Prof Michael Ross (UCLA, California)
• Prof Stephen Lye (Samuel Lunenfeld Research Institute, Toronto, Canada)

Techniques & Facilities

• In vivo rat techniques
  Placental restriction surgery to induce fetal growth restriction
  Embryo transfer techniques (maternal vs fetal influences)
  Cross-foster techniques (prenatal vs postnatal influences)
  Measurement of postnatal milk intake and composition
  Measurement of growth, food intake and body composition
  Rat telemetry and tail-cuff blood pressure
  Intra-arterial glucose tolerance testing and catheter surgery

• In vitro analyses
  Real-time PCR
  In vitro mammary cell culture
  Unbiased sterology to determine nephron number
  Vessel stiffness & reactivity measures
  DXA & pQCT bone analysis
  Histology/immunohistochemistry
  Hormone, metabolite, electrolyte, growth factor measurements
  

Current Student Projects

Amy Mibus (Masters student)
· Placental insufficiency and the consequences for postnatal growth, catch-up growth and adult diseases.

Rachael O'Dowd (PhD student)
· The effect of placental restriction on mammary gland development and lactation.

Nicole Reti (PhD student)
· Regulating human gestational tissue function in health and disease - the critical role of cell death.

Lenka Vodstrcil (PhD student)
· Impact of uteroplacental restriction on relaxin, relaxin receptors and uterine physiology during pregnancy.

Tania Romano (Honours student)
· Intrauterine growth restriction programs reduced bone growth and development

Current projects and research interests

· Fetal growth and placental function
The consequences of placental restriction on placental growth factors, fetal growth and calcium homeostasis are all research focuses of the lab. Using embryo transfer techniques we have identified the key roles of the embryo versus the intrauterine environment in programming growth in the rat.

· Mammary gland development and function
The overall aim of this project is to identify genes that regulate mammary development as well as nutritional quality and quantity of milk and subsequently postnatal growth. Challenges exist for the development of markers of impaired lactation to identify neonates at risk demanding new and innovative basic science approaches. The majority of recent human and experimental research has focused on the prenatal environment as the key period for programming perinatal growth and adult diseases. We have recently identified the lactational environment as critical in programming postnatal growth restriction. We have shown in a novel rat placental restriction model that hormonal regulators of mammary development are reduced which impairs lactation causing perinatal growth restriction. In addition, the role of parathyroid hormone-related peptide (PTHrP) in regulating calcium transfer to milk is being explored.

We are establishing how poor placental function alters the interaction with the mammary gland to impair mammary development before birth and lactation after birth. Using innovative cross-fostering techniques, we will establish how these prenatal and postnatal environments separately and synergistically program growth after birth. Our model system of impaired lactation together with a program of gene discovery will enable development of markers of impaired lactation. These markers will be used in targeted treatments aiming to correct the deficiencies in mammary tissue in vitro and in the rat in vivo. Identification of markers of impaired lactation and low milk quality and quantity in humans will provide options for treatment to benefit neonatal health.

· Cardiovascular disease and the role of the kidney and blood vessels
Being born small and the associated catch-up growth, independently predict adult hypertension. Using our rat placental restriction model, we are determining whether restricting nutrition before birth via the placenta or after birth via lactation increases the risk of developing high blood pressure as well as kidney and blood vessel dysfunction. Manipulations of nutrition after birth will be achieved by cross-fostering studies. We will establish whether a reduction in the number of functioning units (nephrons) in the kidney, alterations in key genes involved in kidney development and changes in blood vessel reactivity are associated with developing hypertension. These studies will identify the mechanisms by which the kidney, vasculature and renin-angiotensin system contribute to the programming of hypertension and the relative roles of the prenatal and postnatal environments.

· Programming of adult diabetes and obesity
The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes. Our novel findings suggest that placental compromise increases appetite but also impairs milk quality and supply which limits overfeeding and catch-up growth initially, but on weaning, may independently lead to diabetes. We will determine if this is a direct result of poor nutrition and made worse by overfeeding in response to restored nutrition after birth or after weaning. We hypothesize that placental compromise permanently reduces an individual's metabolic capacity and that the extent of availability of nutrition after birth determines the consequences for insulin action and increased body fat.

We have found that cross-fostering small rat pups onto mothers with normal lactation improves growth during lactation. Our studies aim to establish the effects of catch-up growth and increased food intake on disease onset. Manipulations of postnatal nutrition (by cross-fostering) and other interventions will help us to identify a developmental stage during which nutritional or other manipulations may have beneficial consequences for the health of the breastfeeding small infant.

· Human pregnancy studies
These studies are aimed at increasing our understanding of the role of the placenta in human pregnancies complicated by intrauterine growth restriction. We are specifically exploring the role of programmed cell death (apoptosis) in fetal membranes. The roles of PTHrP in promoting placental calcium transfer and vascular tone along with its expression in normal and compromised human pregnancy are also being studied.

Recent Publications

Wlodek, ME, Westcott, KT, O'Dowd, R, Serruto, A, Wassef, L, Moritz, KM and Moseley, JM (2005) Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP. Am J Physiol (Regulatory) Jun;288(6):R1620-7, 2005.

Mathai, ML, Soueid, M, Chen, N, Jayasooriya, AP, Sinclair, AJ, Wlodek, ME, Weisinger, HS and Weisinger, RS (2004) Does perinatal omega-3 polyunsaturated fatty acid deficiency increase appetite signalling? Obes Res Nov;12(11):1886-94, 2004.

Lappas, L, Permezel, M, Ho, PW, Moseley, JM, Wlodek, ME, and Rice, GE (2004) Effect of nuclear factor kappa b inhibitors and peroxisome proliferator-activated receptor-gamma ligands on PTHrP release from human fetal membranes. Placenta 25:699-704, 2004.

Briscoe TA, Rehn AE, Dieni S, Duncan JR, Wlodek ME, Owens JA, Rees SM. (2004) Cardiovascular and renal disease in the adolescent guinea pig after chronic placental insufficiency. Am J Obstet Gynecol. 2004 Sep;191(3):847-55.

Lappas M, Permezel M, Ho PW, Moseley JM, Wlodek ME, Rice GE. (2004) Effect of nuclear factor-kappa B inhibitors and peroxisome proliferator-activated receptor-gamma ligands on PTHrP release from human fetal membranes. Placenta. 2004 Sep-Oct;25(8-9):699-704.

Wlodek ME, Di Nicolantonio R, Westcott KT, Farrugia W, Ho PW, Moseley JM. (2004) PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight. Placenta. 2004 Jan;25(1):53-61.

de Gooyer TE, Skinner SL, Wlodek ME, Kelly DJ, Wilkinson-Berka JL. (2004) Angiotensin II influences ovarian follicle development in the transgenic (mRen-2)27 and Sprague-Dawley rat. J Endocrinol. 2004 Feb;180(2):311-24.

Macheda, M.L., Williams, E.D., Best, J.D., Wlodek, M.E. and Rogers, S. (2003) Expression and localisation of GLUT1 and GLUT12 glucose transporters in the pregnant and lactating rat mammary gland. Cell and Tissue Research 2003 311:91-97.

Roberts, C.T., Owens, J.A., Carter, A.M., Harding, J.E., Austgulen, R. and Wlodek, M. (2003) Insulin-like growth factors and fetal programming - a workshop report. Placenta 2003 S72-S75.

Wlodek, M.E., Westcott, K.T., Serruto, A., O’Dowd, R., Wassef, L, Ho, P.W.M. and Moseley, J.M. (2003) Impaired mammary function and parathyroid hormone-related protein during lactation in growth restricted spontaneously hypertensive rats. Journal of Endocrinology 2003 178:233-245.

Wlodek, M.E., Koutsis, K., Westcott, K.T., Ho, P.W.M., Serruto, A., Di Nicolantonio, R. and Moseley, J.M. (2001) The spontaneously hypertensive rat fetus, not the mother, is responsible for its reduced amniotic fluid PTHrP and growth restriction. Placenta 2001 22:646-651.

Di Nicolantonio, R., Koutsis, K. and Wlodek, M.E. (2000) Fetal versus maternal determinants of the reduced fetal and placental growth in SHR. J. Hypertens. 2000 18:45-50.

Curtis, N.E., King, R.G., Moseley, J.M., Ho, P.W.M., Rice, G.E. and Wlodek, M.E. (2000) Preterm fetal growth restriction is associated with increased parathyroid hormone-related protein expression in the fetal membranes. Am. J. Obstet. Gynecol. 2000 183:700-705.

Wlodek, M.E., Westcott, K.T., Ho, P.W.M., Serruto, A., Di Nicolantonio, R., Farrugia, W. and Moseley, J.M. (2000) Reduced fetal, placental and amniotic fluid PTHrP in the growth restricted spontaneously hypertensive rat. Am. J. Physiol. (Regulatory) 2000 279:R31-38.

Farrugia, W., Ho, P.W.M., Rice, G.E., Moseley, J.M., Permezel, M. and Wlodek, M.E. (2000) Parathyroid hormone-related protein (1-34) in gestational fluids and release from gestational tissues. J. Endocrinol. 2000 165:657-662.

Carragounis, A., Koutsis, K., Wlodek, M.E., Berka, J.L.A. and Di Nicolantonio, R. (2000) First report of active renin in rat amniotic fluid. Clin. Exp. Pharmacol. Physiol. 2000 27:631-633.

Farrugia, W., De Gooyer, T.E., Rice, G.E., Moseley, J.M. and Wlodek, M.E. (2000) Parathyroid hormone (1-34) and parathyroid hormone-related protein (1-34) stimulate calcium release from human syncytiotrophoblast basal membranes via a common receptor. J. Endocrinol. 2000 166:689-695.