Department of Physiology - Fetal, Postnatal & Adult Physiology and Disease Research Laboratory

Department of Physiology, Cardiovascular Health Cluster

Interests: The role of prenatal and postnatal environments and the mechanisms involved in the programming of hypertension, diabetes & obesity.

Keywords: Fetus, newborn, programming, adult disease, diabetes, hypertension, growth & development, lactation.

Laboratory Head:	Associate Professor Mary Wlodek
Telephone:	+61 3 8344 8801
Laboratory:	+61 3 8344 9671
Facsimile:	+61 3 8344 5818
Email:	m.wlodek@unimelb.edu.au

Printer friendly version of text [PDF (155KB)]

Our Research Focus

What happens when you are born small?
What is the link between being born small and adult disease?
How does poor milk quality and quantity influence growth and adult disease development?
Are you interested in the perinatal programming of hypertension, diabetes and obesity?
Can we do anything about the pandemic of cardiovascular disease, diabetes and obesity in Western Society?
Do you want to make a difference in medical research?

Small size at birth for gestational age occurs in 10% of human pregnancies in developed societies. This results from restricted growth of the fetus, which primarily reflects a poor environment within the uterus, commonly due to placental insufficiency. Recent human studies have confirmed that being born small is associated with the increased risk of developing adult diseases such as insulin resistance, cardiovascular disease and type 2 diabetes. Growing evidence suggests that the nutrition provided to the baby via the mother’s milk during lactation, and rapid growth of the baby after birth, are both critical factors influencing the programming of adult disease.

Our laboratory has made novel and significant contributions to understanding the importance of the nutritional environment provided by the placenta to the baby before birth and that of the mother’s milk after birth in the programming of adult diseases. We are the first to demonstrate that placental compromise in rats, which causes slow fetal growth, also adversely affects breast development, milk quality and supply, which further impair growth after birth.

We are exploring how a reduction in the number of functioning units (nephrons) of the kidney, alterations in key genes involved in kidney and heart development and changes in blood vessel reactivity are associated with rat offspring born small developing hypertension and cardiovascular disease. Exploring the development of the pancreas and mitochondria of small pups will further our understanding of how and when these offspring develop insulin resistance and diabetes. We are able to manipulate nutrition for a rat pup born small after birth by altering the quality and quantity of nutrition they consume after birth (by cross-fostering) and subsequently exploring disease consequences. We are also exploring the mechanisms that result in abnormal mammary development leading to low milk quality and quantity and aim to develop treatments to improve milk production and growth of offspring.

We aim to identify developmental stages during which nutritional or other interventions may have beneficial consequences. These studies will enable us to identify individuals at increased risk of developing later diseases and provide the scientific basis for the design and testing of appropriately targeted early life interventions. Identification of groups of individuals at risk of developing adult diseases will become increasingly important due to the ever-increasing incidence and earlier age at onset of these diseases.

Lab Members


Name	Title	Position	Year started	Supervisor(s)	Email
Mary Wlodek	Assoc Prof	Head of laboratory			m.wlodek@unimelb.edu.au
Andrew Siebel	Dr	NH&MRC Peter Doherty Fellow	2005	Wlodek	asiebel@unimelb.edu.au
Kerryn Westcott	Mrs	Senior Research Officer (0.8)	2003	Wlodek	westcott@unimelb.edu.au
Andrew Jefferies	Mr	Research Assistant	2007	Wlodek, Westcott	andrewjj@unimelb.edu.au
Rachael O'Dowd	Ms	PhD student	2003	Wlodek, Nicholas	r.o'dowd@pgrad.unimelb.edu.au
Lenka Vodstrcil	Ms	PhD student	2005	Parry, Wlodek	l.vodstrcil@pgrad.unimelb.edu.au
Marc Mazzuca	Mr	PhD student	2006	Wlodek, Tare, Moritz	m.mazzuca2@pgrad.unimelb.edu.au
Tania Romano	Ms	PhD student	2007	Wlodek, Wark	t.romano@pgrad.unimelb.edu.au
Rhianna Laker	Ms	PhD student	2007	Wlodek, McConell, Wadley	r.laker@pgrad.unimelb.edu.au
Yu May Soh	Ms	PhD student	2008	Parry, Wlodek, Conrad	y.soh2@pgrad.unimelb.edu.au
Linda Gallo	Ms	Honours student	2008	Siebel, Wlodek, McConell	l.gallo@unimelb.edu.au
Emma Simpson	Ms	Honours student	2008	Wlodek, Parry, Westcott	e.simpson2@ugrad.unimelb.edu.au
Brianne Lauritz	Ms	Honours student	2008	Wlodek, Siebel	b.lauritz@ugrad.unimelb.edu.au

Achievements of Current Research Group Members

Assoc Prof Mary Wlodek – Recent Invited International / National Presentations

2008	What happens when you are born small? Health and Medical Sciences Conference & International Postgraduate Convention. Penang, Malaysia.
2008	What are the critical nutritional environments for small babies in the programming of growth and disease? Fetal Physiology Symposium; Society For Gynecological Investigation. San Diego, CA, USA.
2007	Role of the perinatal environment in the programming of adult diseases. Perinatal Society of Australia and New Zealand. Melbourne, Australia.
2007	The postnatal environment is critical for the programming of adult diseases. International Congress on Developmental Origins of Health and Disease. Perth, Australia.
2006	Placental effects on lactation, growth and adult diseases. Experimental Biology 2006, American Society for Nutrition Presidential Symposium on Novel concepts in the developmental origins of adult health and disease. San Francisco, USA.
2006	The role of the prenatal and postnatal environments in the programming of growth and cardiovascular disease. International Society of Hypertension Satellite Symposium, International Symposium on Lifestyle Related Diseases- Perspectives for Primary Prevention and Treatment in Animal Models and Humans, Nishinomiya, Japan.
2005	Effect of uteroplacental insufficiency on mammary function, milk composition and neonatal growth and their consequences for growth and adult disease development. Society For Gynecological Investigation Minisymposium on Regulation of Breast Development and Lactational Function. Los Angeles, CA, USA.
2005	Placental and mammary programming adult diseases. International Union of Physiological Sciences (IUPS) Satellite Symposia on The prenatal environment, programming and postnatal consequences. San Diego, CA, USA.

Assoc Prof Mary Wlodek – Invited Research Seminars

2008	Department of Pathology, The University of Melbourne, Australia
2008	Department of Anatomy & Cell Biology, The University of Melbourne, Australia
2007	Department of Physiology, The University of Melbourne, Melbourne, Australia
2007	Mothers & Babies Research Centre, University of Newcastle, Newcastle, Australia
2007	Department of Anatomy and Cell Biology, Monash University, Melbourne, Australia
2006	Centre for Obesity Research and Education, Monash Univ, Melbourne, Australia
2006	Department of Physiology, Monash University, Melbourne, Australia
2006	Department of Zoology, The University of Melbourne, Australia
2005	Perinatal Society of Australia and New Zealand Thorburn Visiting Professor Symposium on Fetal Growth: An experimental and clinical workshop, Melbourne, Australia
2005	Garvan Institute of Medical Research, Sydney, Australia

Assoc Prof Mary Wlodek – Other Achievements
Associate Dean, Melbourne School of Graduate Research (Oct 2007 – Dec 2009)
Chair of newly formed Central University Committee Melbourne School of Graduate Research Supervisor Programs Advisory Committee
Re-elected University Research Higher Degrees Committee 2007-2009
Elected to Departmental Committee 2007
Co-Convenor Post Graduate Students 2007

Evidence of National and International research profile is provided by meetings at which staff and students have presented abstracts with oral presentations indicated.
Conference Abbreviations: Australian Health and Medical Research Council (AHMRC); Australian Society for Medical Research (ASMR); Developmental Origins of Health and Disease (DOHAD); US Endocrine Society (ENDO); Endocrine Society of Australia (ESA); Fetal and Neonatal Physiology Symposium (FNPS); International Congress on Obesity (ICO); International Symposium on Resistance Arteries (ISRA); Network for Genes & Environment in Development (NGED); Perinatal Society of Australia and New Zealand (PSANZ); Society for Gynecologic Investigation (SGI); Society for Reproductive Biology (SRB); Society for the Study of Reproduction (SSR).

Dr Andrew Siebel

NHMRC Peter Doherty Fellowship 2005 – 2009
Chair - Early Career Researcher Committee of ARC Research Network in Genes Environment in Development 2006-2007
Chair organizing committee for NGED ECR Conference, North Stradbroke Island, November 2007
NGED Travel Award: SGI 2007 ($1,000)
Coordinator Postdoctoral Group, Department of Physiology
Finalist in President’s Poster session (top 8% of posters), International Congress on Obesity, 2006
National competitive grant - ANZ Trusts William Buckland Foundation for 2007
Two successful University of Melbourne ECR grants in 2006 & 2008
CASS Foundation Travel Grant $3,500 & ESA-Ipsen International Travel Award $3,500 San Francisco & Los Angeles 2008

Abstracts – DOHAD 2005; ICO 2006; SGI 2007; PSANZ oral 2007; DOHAD oral 2007; NGED oral 2007; ENDO 2008

Publication – J. Am. Soc. Nephrol. 2007; Endocrinology 2008; Am. J. Physiol. 2008; Kidney Int. 2008; Reprod Sci 2008

Mrs Kerryn Westcott

Promotion from Research Assistant to Senior Research Officer in 2006 based on her significant contributions to research, role in supervision of research students and leadership within the laboratory group
First senior author publication in press
NGED Travel Award: DOHAD 2007 ($500)

Abstracts – ASMR 2003; ESA oral 2006; DOHAD oral 2007

Publications – J. Endocrinol. 2003; Placenta 2004; Am. J. Physiol. 2005; Physiol. Behav. 2005; Clin. Exp. Pharmacol. Physiol. 2006; Kidney Int. 2008; Endocrinology 2008; Neuroendocrinology 2008 (Westcott as first author); Reprod Sci 2008

Ms Rachael O’Dowd

Finalist, Novartis Junior Investigator Oral Session (top 10% of abstracts) , Endocrine Society of Australia, 2006. Postnatal growth is improved by cross-fostering a pup born small onto a mother with normal lactation by altering alveolar area, milk production and milk protein gene expression
Writing PhD thesis (working full-time in Department of Anatomy & Cell Biology)

Abstracts – PSANZ oral 2004; PSANZ oral 2005; FNPS oral 2005; ESA oral 2006

Publications – Am. J. Physiol. 2007; Am. J. Physiol. 2008; Reprod. Fert. Develop; Reprod Sci 2008

Ms Lenka Vodstrcil

NH&MRC Dora Lush Postgraduate Scholarship 2006 – 2008
NGED Travel Award: SGI 2007 ($1,000)
John and Allan Gilmour Award from the Faculty of Science 2008 ($4,500)

Abstracts – SGI 2005; SRB oral 2006; SGI 2007; PSANZ 2007; SRB oral 2007; NGED oral 2007; Relaxin 2008 oral & poster; SSR 2008; SRB oral 2008 (Young Investigator Award session)

Publications – Reprod. Fert. Develop. 2007; Adv. Exp. Med. Biol. 2007

Mr Marc Mazzuca

Kidney Health Australia Biomedical Research Scholarship 2007 – 2008
Melbourne International Fee Remission Scholarship (MIFRS) 2006 – 2008
SGI Medical and Graduate PhD Student Stipend for Research in Reproduction 2007
NGED Travel Awards: SGI 2007 ($1,000); DOHAD 2007 ($500)
New Investigator Award for the Best Oral Presentation in the Basic Science Discipline (student or <5 years post PhD), PSANZ 2007
Bioline Student Award for best oral presentation, NGED ECR Conference 2007
NGED Annual Forum 2008 - Invited Talk "NGED's contribution to my PhD and implications to my research" & ECR Forum: "Progressing through 1st and 2nd year of my PhD"
International Symposium on Resistance Arteries (ISRA) - Oral presentation 2008

Abstracts – SGI 2007; PSANZ oral 2007; DOHAD 2007; NGED oral 2007; ISRA oral 2008

Ms Tania Romano

Geoffrey Gardiner Dairy Foundation Scholarship 2007 – 2008
MDHS Univ of Melbourne, Faculty Research Scholarship 2008
NGED Travel Award: ANZBMS 2007 ($1,000)
ANZBMS 2007 Student Travel Grant $552
DOHAD 2007 Early Career Research Award for best abstract $500

Abstracts – AHMRC 2006; SGI 2007; PSANZ oral 2007; DOHAD oral 2007; NGED oral 2008

Ms Rhianna Laker

Faculty of Medicine, Dentistry and Health Sciences, Univ of Melbourne, Lowe Scholarship 2007
NHMRC/NHF Dora Lush Postgraduate Scholarship 2008 – 2010
NGED Travel Award: DOHAD 2007 ($500)

Abstracts – DOHAD 2007

Ms Yu May Soh

Melbourne International Fee Remission Scholarship (MIFRS) 2008 – 2011
Science Faculty Scholarship (SFS) 2008 – 2011

Abstracts – Relaxin oral 2008; SRB oral 2008

Recent grant income (2006 - current)


Description	Chief investigators	Granting body	Year(s)	Amount (AUD)
Intergenerational programming of cardiovascular disease for babies born small: pathways and prevention	ME Wlodek KM Moritz M Tare LJ Parry HC Parkington	March of Dimes Foundation	2008-2011	$US 276,352
Are postnatal nutrition and the intrauterine environment important for early skeletal muscle development and function?	ME Wlodek AL Siebel GK McConell GD Wadley	Diabetes Australia Research Trust	2008	50,000
Development of the endocrine pancreas is regulated by nutritional environments	AL Siebel	Uni of Melb ECR Grant Scheme	2008	25,000
Medical and Graduate PhD Student Stipend for Research in Reproduction	ME Wlodek M Mazzuca	Society for Gynecologic Investigation	2007	$US 2,000
Can exercise and improved nutrition normalise rat skeletal muscle mitochondrial biogenesis following growth restriction?	G McConell ME Wlodek G Wadley	NH&MRC Project Grant	2007-2009	325,065
Can exercise and improved nutrition normalise myocardial mitochondrial biogenesis following fetal growth restriction in rats?	G Wadley ME Wlodek G McConell	National Heart Foundation	2007-2008	122,887
Being born small programs gestational diabetes and poor milk quality: mechanisms for the transmission of diabetes to the next generation	ME Wlodek JA Owens AL Siebel	Diabetes Australia Research Trust	2007	50,000
Optimising the bone response to dietary calcium: a physiological approach	ME Wlodek J Wark D Myers	Geoffrey Gardiner Dairy Foundation	2007	96,000
Development and function of the pancreas is compromised in growth-restricted offspring	AL Siebel ME Wlodek	ANZ Trusts William Buckland Foundation	2007	9,750
Regulation of uterine artery function during pregnancy and impact on fetal development	LJ Parry ME Wlodek	University of Melbourne Research Grant	2007	24,000
Prenatal placental and postnatal mammary programming of cardiovascular and renal diseases	ME Wlodek KM Moritz M Tare	NH&MRC Project Grant	2006-2008	492,750
Perinatal and intergenerational influences on adult diabetes	ME Wlodek	NH&MRC Project Grant	2006-2008	429,750
Intrauterine growth restriction programs reduced bone growth and development in rats	ME Wlodek J Wark JA Owens D Myers H Morris	Eli Lilly Endocrinology Research Grant	2006	25,000
Maternal calcium supplementation and prevention of diabetes in offspring born small	JA Owens ME Wlodek JS Robinson CA Crowther	Diabetes Australia Research Trust	2006	45,000
Being born small and the intergenerational programming of diabetes	ME Wlodek	Melbourne Research Grants Scheme	2006	30,000
Diabetes is programmed in small babies by the nutritional environment	AL Siebel	MDHS Early Career Grant	2006	27,422

Established Research Collaborations

Perinatal Programming of Disease Research

Perinatal programming of adult metabolic diseases
Prof Julie Owens, Dept of Obstetrics and Gynaecology, Univ of Adelaide, SA

Placental & lactational restriction and the programming of hypertension – the role of the kidney
Dr Karen Moritz, Dept of Anatomy & Cell Biology, Monash Univ, Melbourne, VIC

Placental & lactational restriction and the programming of hypertension – Role of blood vessel stiffness & reactivity
Dr Marianne Tare and A/Prof Helena Parkington, Dept of Physiology, Monash Univ, Melbourne, VIC

Role of mitochondrial biogenesis in the programming of diabetes
Drs Glenn McConell and Glenn Wadley, Dept of Physiology, Univ of Melbourne, Melbourne, VIC
A/Prof Greg Cooney, Garvan Institute of Medical Research, Sydney, NSW

Placental & lactational restriction and the programming of reduced bone mineral density
Prof John Wark, Dept of Medicine, Univ of Melbourne, Melbourne, VIC
Prof Howard Morris, Hanson Institute, Adelaide, SA

Cardiomyocyte development in growth-restricted offspring
Dr Jane Black, Dept Anatomy & Cell Biology, Monash University, VIC

Pregnancy, Lactation & Reproductive Research

The effect of placental restriction on mammary gland biology
Dr Kevin Nicholas, Dept of Zoology, Univ of Melbourne, Melbourne, VIC

Impact of placental restriction on reproductive relaxin and relaxin receptors
Dr Laura Parry, Dept of Zoology, Univ of Melbourne, Melbourne, VIC
Prof Kirk Conrad, Dept of Physiology and Functional Genomics, Univ of Florida, Florida, USA

Uterine and steroid regulation of reproductive relaxin and relaxin receptors
Prof Stephen Lye & Dr Oksana Shynlova, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

Placental restriction alters fetal and neonatal brain neurosteoids
Dr Jon Hirst, School of Biomedical Sciences, Univ of Newcastle, NSW
A/Prof David Walker, Dept of Physiology, Monash Univ, Melbourne, VIC

Techniques & Facilities

In vivo & in vitro rat techniques

Uteroplacental insufficiency 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 & intra-peritoneal glucose tolerance testing and catheter surgery
Exercise training
24 hour renal function studie
Real-time PCR
In vitro mammary cell culture
Unbiased sterology to determine nephron number (off-site)
Vessel stiffness & reactivity measures (off-site)
DXA & pQCT bone analysis (off-site)
Histology/immunohistochemistry
Hormone, metabolite, electrolyte, growth factor measurements

Major Research Projects and Interests

Experimental model
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 accelerated growth following placental restriction in an established rat model. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. Uteroplacental insufficiency and fetal growth restriction is induced in Wistar-Kyoto rats by ligating the uterine vessels on day 18 of pregnancy. 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.
We have found that cross-fostering small rat pups onto mothers with normal lactation improves growth during lactation. 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 small infant.

Fetal growth and placental function and the role of relaxin
A key feature of mammalian reproduction is the development of the embryo and fetus within the reproductive tract of the mother, giving the young better protection and allowing it to reach an optimal size at birth. Efficient placental function depends critically on the unrestricted flow of maternal blood to the placenta. Disruption to placental blood flow can lead to restricted fetal growth and places the offspring at increased risk of developing adult diseases. 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.
Surprisingly few studies have investigated the acute effects of restricting maternal blood flow to the placenta on the ovary and uterus during pregnancy. As the ovary and maintenance of a viable uterine environment are both crucial aspects of pregnancy, disruption to either could have a significant negative impact on the well-being of the fetus, including growth. We have recently showed that restricting placental blood flow in late pregnant rats leads to a decrease in the amount of relaxin (RLX - peptide hormone) protein in the ovary and an increase in the receptors for RLX in the uterus. These data provide new evidence to link restricted placental function with a disruption to both ovarian function (production and release of hormones) and expression of receptors in the uterus. The overall aim of this project is to demonstrate a role for an important growth factor, RLX, in maintaining adequate uteroplacental blood flow during pregnancy. It will also characterise changes in RLX-related ovarian and uterine physiology that could affect fetal growth in late gestation.

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 are establishing how poor placental function alters the interaction with the mammary gland to impair mammary development before birth and lactation after birth. We have shown in a novel rat placental restriction model that hormonal regulators of mammary development are reduced inducing premature lactogenesis (alteration in milk protein gene expression) 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.
Using innovative cross-fostering techniques, we are establishing 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 heart, kidney and blood vessels
Being born small and the associated accelerated growth, independently predict adult hypertension and cardiovascular disease. 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 heart, kidney and blood vessel dysfunction. Manipulations of nutrition after birth are achieved by cross-fostering studies. We have shown that growth-restricted pups fostered on to a mother with impaired lactation have a lower nephron number, high blood pressure and impaired vessel reactivity as adults when compared to Control – on – Control offspring. Most importantly, when these growth-restricted pups (compromised in utero environment) are cross-fostered on to Control mothers (normal lactational environment) they had restored nephron endowment, blood pressure and vessel reactivity. We will further establish whether a reduction in the number of functioning units (nephrons) in the kidney, alterations in key genes involved in kidney and heart development as well as adult renal and cardiovascular function and changes in blood vessel reactivity and stiffness are associated with developing cardiovascular disease. These studies will identify the mechanisms by which the kidney, heart and vasculature contribute to the programming of cardiovascular disease and the relative roles of the prenatal and postnatal environments.

Programming of adult diabetes, obesity & osteoporosis
The aim of this aspect of our research is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes, obesity and osteoporosis. Our novel findings suggest that uteroplacental insufficiency impairs milk quality and supply which limits overfeeding and accelerated growth initially, but on weaning, may independently lead to diabetes and obesity. 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. Our recent studies are exploring whether restriction nutrient supply before birth via the placenta, or after birth via the mother’s milk (by cross-fostering) increases the risk of reduced bone density and growth as well as increasing overall fat mass. The relationship between sex hormones and skeletal development and key bone markers will also be assessed to establish the link between programming bone growth and reproductive maturation with gender specific effects. Identification of novel populations at risk of developing osteoporosis, and increased incidence of bone fractures, is increasingly important due to the rising incidence of this under-diagnosed disorder.
Intrauterine growth restriction, commonly arising from a poorly functioning placenta, increases the risk of insulin resistance and adult diabetes. One of our aims is to determine the effect of placental restriction and its associated lactational restraint on glucose tolerance, insulin secretion and markers of adiposity and skeletal muscle mitochondrial biogenesis in adult offspring. We have found that placental restriction impairs adult glucose homeostasis and induces fasting and second phase hyperinsulinaemia. In males, placental restriction reduces key markers of mitochondrial biogenesis in skeletal muscle. Furthermore, our data highlight the importance of the postnatal lactational environment as a major determinant of later metabolic phenotype.

Key Research Outcomes to Date

Established that uteroplacental insufficiency in a rat model of growth restriction directly impairs mammary development during pregnancy, which consequently compromises milk quality and quantity after birth, further restricting postnatal growth for pups born small.
Using a unique approach, our recent cross-fostering studies have unequivocally proven that both prenatal growth restriction and postnatal mammary function independently influence postnatal growth, the extent of accelerated growth following uteroplacental insufficiency and susceptibility to a host of adult diseases.
Identified that sex differences and alterations in reproductive maturation play an important role in the programming of adult diseases (hypertension, obesity, diabetes and osteoporosis).

Future Directions

Further characterize the mechanisms by which uteroplacental insufficiency impairs mammary development and identify additional markers of impaired lactation as well as developmental stages during which time interventions may have beneficial consequences for lactational performance.
Identify the relative roles of the prenatal placental and postnatal lactational environments, using cross-fostering, in the programming of adult diseases including hypertension, obesity, osteoporosis and diabetes.
Identify the role of the pancreas in programming insulin resistance and Type 2 diabetes.
Identify potential interventions and treatments, as well as elucidate mechanisms, contributing to the programming of adult diseases (hypertension, diabetes, cardiovascular disease, osteoporosis and obesity).

Recent publications

Wlodek, M.E., Ceranic, V., O’Dowd, R., Westcott, K.T., and Siebel, A.L. Maternal progesterone treatment rescues the mammary impairment following uteroplacental insufficiency and improves postnatal pup growth in the rat. Reprod Sci In press accepted July 8, 2008.

Pascoe K.C., Wlodek M.E. and Jones, G.T. Increased elastic tissue defect formation in the growth restricted Brown Norway rat: a potential link between in utero condition and cardiovascular disease? Pediatr Res 64:125-130, 2008.

Westcott, K.T., Hirst, J.J., Ciurej, I., Walker, D.W., Wlodek, M.E. Brain allopregnanolone concentrations in the fetal and postnatal rat fetus and pup in response to uteroplacental insufficiency. Neuroendocrinology DOI: 10.1159/000139771, 2008.

Siebel, A.L., Mibus, A.L., De Blasio, M.J., Westcott, K.T., Morris, M.J., Prior, L., Owens, J.A. and Wlodek, M.E. Improved lactational nutrition and postnatal growth ameliorates impairment of glucose tolerance by uteroplacental insufficiency in male rat offspring. Endocrinology 149:3067-3076, 2008.

Wadley, G.D., Siebel, A.L., Cooney, G.J., McConell, G.K., Wlodek, M.E. and Owens, J.A. Uteroplacental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex specific manner in the adult rat. Am J Physiol (Endocrinol Metab) 294:E861-E869, 2008.

Needham, B.E., Wlodek, M.E., Ciccotosto, G.D., Fam, B.C. Masters, C.L., Proietto, J. Andrikopoulos, S. Cappai, R. Identification of the Alzeimer’s disease amyloid precursor protein (APP) and its homolog APLP2 as essential modulators of glucose and insulin homeostatsis and growth. J Pathol 215:155-163, 2008.

O’Dowd, R., Wlodek, M.E. and Nicholas, K.R. Uteroplacental insufficiency alters the mammary gland response to lactogenic hormones in vitro. Reprod. Fert. Develop. 20:460-465, 2008.

Wlodek, M.E., Westcott, K.T., Siebel, A.L., Owens, J.A. and Moritz, K.A. Growth restriction induced before or after birth reduces nephron number and increases blood pressure in male rats. Kidney International 74:187-195, 2008.

O’Dowd, R.A., Kent, J.C., Moseley, J.M. and Wlodek, M.E. The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth. Am J Physiol (Regul Integr Comp Physiol) 294: R539-R548, 2008 [PDF (1,500KB)].

Ping, S., Trieu, J., Wlodek, M. and Barrett, G. The effects of estrogen on basal forebrain cholinergic neurons and spatial learning. J Neurosci Res In Press accepted Oct 31, 2007.

Wlodek , M.E., Mibus, A.L., Tan, A., Siebel, A.L., Owens, J.A. and Moritz, K. A normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J Am Soc Nephrol 18:1688-1696, 2007 [PDF (185KB)]
Subject of “JASN This Month’s Highlights” J Am Soc Nephrol18:1617-1618, 2007 [PDF (110KB)] and the “JASN Editorial”J Am Soc Nephrol18:1626-1629, 2007 [PDF (56KB)].

Vodstrcil, L.A., Wlodek, M.E., Parry, L.J. The effects of uteroplacental restriction on the relaxin-family receptors, Lgr7 and Lgr8, in the uterus of late pregnant rats. Reprod Fert Develop 19:530-538, 2007 [PDF (303KB)].

Reti, N.G., Lappas, M., Berthold, H. Riley, C., Wlodek, M.E., Henschke, P., Permezel, M., Walker, S., Rice, G.E. The effect of high oxygen on placental function in short term explant cultures. Cell Tissue Res 328:607-616, 2007 [PDF (431KB)].

Reti, NG, Lappas, M, Riley, C, Wlodek, ME, Permezel, M, Walker, S, Rice, GE. Why do membranes rupture at term? Evidence of increased cellular apoptosis in the supra-cervical fetal membranes. Am J Obstet Gynecol 196: 484.e1-484.e10, 2007 [PDF (2,743KB)].

Di Nicolantonio, R, Koutsis, K, Westcott, KT and Wlodek, ME. Relative Contribution of the prenatal versus postnatal period on development of hypertension and growth rate of the Spontaneously Hypertensive Rat. Clin Exp Pharmacol Physiol 33:9-16, 2006 [PDF (194KB)].

Di Nicolantonio, R, Koutsis, K, Westcott, KT and Wlodek, ME. Lack of evidence for a role for either the in utero or suckling periods in the exaggerated salt preference of the Spontaneously Hypertensive Rat. Physiology & Behavior 86:500-507, 2005 [PDF (135KB)].

Wlodek, ME, Westcott, KT, O’Dowd, R, Serruto, A, Wassef, L, Moritz, KM and Moseley, JM. 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 [PDF (653KB)].

Mathai, ML, Soueid, M, Chen, N, Jayasooriya, AP, Sinclair, AJ, Wlodek, ME, Weisinger, HS and Weisinger, RS. Does perinatal omega-3 polyunsaturated fatty acid deficiency increase appetite signalling? Obes Res Nov;12(11):1886-94, 2004 [PDF (116KB)].

Lappas, L, Permezel, M, Ho, PW, Moseley, JM, Wlodek, ME, and Rice, GE. 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 [PDF (151KB)].

Briscoe TA, Rehn AE, Dieni S, Duncan JR, Wlodek ME, Owens JA, Rees SM. Cardiovascular and renal disease in the adolescent guinea pig after chronic placental insufficiency. Am J Obstet Gynecol Sep;191(3):847-55, 2004 [PDF (552KB)].

Wlodek ME, Di Nicolantonio R, Westcott KT, Farrugia W, Ho PW, Moseley JM. PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight. Placenta Jan;25(1):53-61, 2004 [PDF (155KB)].

de Gooyer TE, Skinner SL, Wlodek ME, Kelly DJ, Wilkinson-Berka JL. Angiotensin II influences ovarian follicle development in the transgenic (mRen-2)27 and Sprague-Dawley rat. J Endocrinol Feb;180(2):311-24, 2004 [PDF (1,270KB)].

Macheda, M.L., Williams, E.D., Best, J.D., Wlodek, M.E. and Rogers, S. Expression and localisation of GLUT1 and GLUT12 glucose transporters in the pregnant and lactating rat mammary gland. Cell and Tissue Research 311:91-97, 2003 [PDF (412KB)].

Wlodek, M.E., Westcott, K.T., Serruto, A., O’Dowd, R., Wassef, L, Ho, P.W.M. and Moseley, J.M. Impaired mammary function and parathyroid hormone-related protein during lactation in growth restricted spontaneously hypertensive rats. J Endocrinol 178:233-245, 2003 [PDF (271KB)].

Wlodek, M.E., Koutsis, K., Westcott, K.T., Ho, P.W.M., Serruto, A., Di Nicolantonio, R. and Moseley, J.M. The spontaneously hypertensive rat fetus, not the mother, is responsible for its reduced amniotic fluid PTHrP and growth restriction. Placenta 22:646-651, 2001 [PDF (116KB)].

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

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

Wlodek, M.E., Westcott, K.T., Ho, P.W.M., Serruto, A., Di Nicolantonio, R., Farrugia, W. and Moseley, J.M. Reduced fetal, placental and amniotic fluid PTHrP in the growth restricted spontaneously hypertensive rat. Am J Physiol (Regulatory) 279:R31-38, 2000 [PDF (629KB)].

Farrugia, W., Ho, P.W.M., Rice, G.E., Moseley, J.M., Permezel, M. and Wlodek, M.E. Parathyroid hormone-related protein (1-34) in gestational fluids and release from gestational tissues. J Endocrinol 165:657-662, 2000 [PDF (109KB)].

Carragounis, A., Koutsis, K., Wlodek, M.E., Berka, J.L.A. and Di Nicolantonio, R. First report of active renin in rat amniotic fluid. Clin Exp Pharmacol Physiol 27:631-633, 2000 [PDF (85KB)].

Farrugia, W., De Gooyer, T.E., Rice, G.E., Moseley, J.M. and Wlodek, M.E. 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 166:689-695, 2000 [PDF (117KB)].

Study and Employment Opportunities
We have many opportunities for students to join our lab, including vacation scholarships, 3rd year, Honours and postgraduate research projects. We also take expressions of interest from potential post-doctoral fellows competitive for independent funding. Please contact Assoc Prof Mary Wlodek (m.wlodek@unimelb.edu.au) or Dr Andrew Siebel (asiebel@unimelb.edu.au) for more information.

Faculty of Medicine, Dentistry and Health Sciences Department of Physiology

Menu