Early Life Programming of Health and Disease
Contact
Information
Staff, Students and Current Research Projects
| Name |
Position |
| Prof Julie Owens |
Group Leader |
| Dr Kathy Gatford |
Research Fellow |
| Dr Miles DeBlasio |
Post-doctoral research fellow |
| Pat Grant |
Research Officer |
| Lyn Harland |
Research Officer |
| Tasma How |
Technical Assistant |
| Simon Moretta |
Technical Assistant |
| Wee-Ching Kong |
PhD Student |
| Saidatul Mohammad |
Honours student |
Internal Collaborators
Professor Jeffrey Robinson
A/Professor Claire Roberts
Professor Caroline Crowther
A/Professor Prof David Kennaway
External Collaborators
A/Professor Mary Wlodek, University of Melbourne
A/Professor Michael Symonds, University of Nottingham
A/Professor Ruth Morley, Murdoch Children’s Research Institute
A/Professor Marie Dziadek, University of Auckland
Dr Miodrag Dodic and Prof Marelyn Wintour, Monash University
Research Interests
Pregnancy, Early Growth and Development and Adult Health
Our research has two major streams where we seek to increase fundamental knowledge
about early growth and development and how it is altered in major disease states,
especially fetal growth restriction, then to apply this to the design and testing
of interventions:
- What controls fetal growth and functional development, specifically, the roles
of the mother, placenta, and the insulin-like growth factors?
- What are the initiating events in utero and in infancy, and the mediating
mechanisms involved, whereby the early life environment influences our later metabolic
and cardiovascular homeostasis?
Maternal, placental and endocrine influences on fetal growth
The mother’s capacity to acquire nutrients and oxygen from the external
environment and placental delivery of these to the developing fetus is a major
determinant of fetal growth, development and survival (25, 34). Our recent focus
is defining the role of the maternal insulin-like growth factor (IGF) axis in
this, and we have shown that it is subject to metabolic and endocrine regulation
and acts on (a) adaptation of maternal organs and tissues to pregnancy, (b) substrate
partitioning between mother and conceptus and (c) placental growth and function
(6, 14, 16, 20, 22, 32).
We have further shown that increased IGF-I or IGF-II abundance in the mother
can promote placental growth and fetal growth (20) and in collaboration with Claire
Roberts, are investigating the mechanisms involved. We also seek to identify the
major maternal sources of IGFs and their modulatory binding proteins during pregnancy
and the factors that alter their expression (6).
Currently, there are few effective approaches to prevention or treatment of
placental insufficiency and restricted fetal growth and its associated increased
perinatal morbidity and mortality. Our broad aim is to develop and test direct
and indirect approaches to modulating the maternal IGF axis to prevent or overcome
this.
We have also shown for the first time, that increasing IGF-I abundance in the
fetus promotes growth, maturation and function of particular fetal organs and
placental functional development (23-24, also see Lok et al). Because each IGF
has distinct as well as common actions, defining these more fully in the fetus
and in fetal growth restriction may reveal novel approaches to restoration of
fetal and placental functional development.
Early life and programming of adult health
The environment before birth and in infancy and early childhood is increasingly
recognised as strongly influencing adult health and risk of certain diseases.
Small size at birth for gestational age, reflecting restricted fetal growth, and
its associated ‘catch-up’ growth, substantially increase the risk
of insulin resistance, diabetes, obesity and related disorders (see Book, 38-41).
Restriction of placental supply of essential oxygen and nutrients is a major
cause of small size at birth. We have shown that placental restriction and fetal
growth restriction lead to impaired insulin action and diabetes, hypertension
and atherosclerosis in adult offspring in several species (3, 10, 13, 15, 17,
31, 36). We have also demonstrated directly that the ‘catch-up’ or
accelerated growth that occurs in infancy following restricted fetal growth independently
predicts later insulin resistance, obesity, diabetes and hypertension (3, 4, 13,
15).
The nature of the specific disturbance(s) induced by placental restriction
and involved in ‘catch-up’ growth to initiate this ‘programming’
of adult dysfunction is unknown and we currently lack effective interventions
to prevent or ameliorate this. We therefore seek to identify the initiating factors
and define the pathways and mechanisms by which perinatal and infancy factors
lead to adult dysfunction and disease (1, 2, 4, 5, 7, 8, 14, 17, 21, 28-30, 35,
37). With this knowledge, we have begun to design and test possible interventions
and treatments for eventual use in clinically and in public health.
Maternal & Fetal Biology & Medicine
Regulation of growth and development of the fetus and placenta
Dr Vivienne Moore and Professor Jeffrey Robinson
with Dr Julie Owens
- Nutrition and metabolism of mothers during pregnancy and fetal growth
- Placental and fetal growth and development
- Regulation of embryonic and fetal growth by hormones and growth factors
- Fetal origins of adult diseases
Current Projects:
Maternal insulin-like growth factors (IGFs): impact on placental function
and fetal growth and survival
An important role for placentally produced IGF-II has been shown in rodents, however
in women and other larger mammalian species, pregnancy greatly increases the circulating
levels of IGF-I, IGF-II as well as IGF-I, and that of IGF-binding proteins in
the mother and these each correlate strongly with placental function. The maternal
tissues responsible for increased IGF production and altered IGBP production in
pregnancy are mostly unknown however.
We are currently determining the effect of pregnancy on expression of IGF-I
and –II and IGFBPs 1-4 in maternal organs and tissues in the guinea pig.
Mid and late pregnancy, when placental growth and fetal demand are greatest and
maternal undernutrition, which increases competition between maternal tissues
and the conceptus, will be studied. The tissue expression of IGFs and IGFBPs will
be related to maternal blood levels, placental functional parameters and fetal
growth and survival.
This will identify the maternal tissue sources of the major elements of the
IGF axis that best predict placental function and fetal growth and survival. The
known and putative factors responsible for increased or altered expression of
IGFs and IGFBPs in maternal tissues during pregnancy will then be targeted in
potential approaches to treatment of placental insufficiency and fetal growth
restriction.
Insulin-like growth factors: fetal supplementation and impact on prenatal and
postnatal growth, survival and function
The impact of fetal supplementation with IGFs via different routes, on prenatal
and postnatal growth, survival and functional development is being compared and
contrasted.
The impact of intravascular IGF-I and IGF-II supplementation on placental function
and fetal growth and maturation in late gestation is being defined in the normally
growing and placentally restricted sheep. The mechanisms involved are also being
examined, including effects on partitioning of nutrients and oxygen between the
placenta and fetus and the fetal endocrine state.
These outcomes are being compared with intra-amniotic IGF-I supplementation,
where the effects on perinatal survival and postnatal growth and metabolic homeostasis,
body composition and endocrine function are also under study.
Prenatal programming of adult diabetes: molecular and cellular defects?
A poor intrauterine environment, with restricted supply of oxygen and/ or nutrients,
induces persistent changes in insulin secretion and sensitivity, resulting in
diabetes in later life. We currently understand little about the underlying defects
induced at the cellular and molecular level in key tissues by prenatal programming
and therefore what the adverse environment before birth is targeting.
Mitochondrial dysfunction and intracellular lipid accumulation in skeletal
muscle and liver has emerged as a major characteristic of human and experimental
insulin resistance and diabetes. These may also cause impaired insulin secretion
by the beta cell within the pancreas. We have recently identified for the first
time, similar defects in the adult that was small at birth, using the guinea pig.
We are currently investigating whether this defect actually causes prenatally
induced insulin resistance, what specific molecular and cellular determinants
of mitochondrial function and lipid homeostasis have been altered and when during
development. The efficacy of treatment with an enhancer of lipid metabolism in
infancy to prevent the emergence of insulin resistance and diabetes in the young
or in the adult to reverse it following fetal growth restriction is also being
tested.
If proven to be effective, this approach can be considered for testing in humans
where drugs with such properties have long been used in treatment of hyperlipidaemia.
Prenatal programming of adult diabetes: systemic defects?
The early life environment may program later dysfunction and increased risk of
disease, in part by inducing persistent alterations in major endocrine and neuroendocrine
axes, such as the somatotropic axis (growth hormone and the insulin-like growth
factors), the hypothalamo-pituitary adrenal axis, the adipoinsular axis including
leptin and the sympathetic nervous system (see Book).
We are investigating the impact of placental restriction of fetal growth on
expression and activity of the growth hormone and insulin-like growth factor axis
in postnatal life and its relationship to development of obesity, impaired insulin
action and diabetes. We have demonstrated persistent IGF deficiency and altered
metabolic responsiveness to IGFs following prenatal restraint coupled with GH
deficiency or resistance depending upon sex and are going onto define the molecular
basis of these changes in key tissues and their time of onset from before birth.
Their associations with altered insulin secretion, sensitivity and growth of skeletal
muscle and adipose tissue is also under study.
We have also begun to characterise the consequences of placental restriction
of fetal growth for other regulatory systems, to evaluate their contributions
to later metabolic and cardiovascular dysfunction.
Maternal calcium supplementation and prevention of diabetes in offspring
born small.
One candidate for the initiation of programming of later diabetes is perturbed
perinatal calcium status. We have recently shown that placental restriction of
fetal growth in the rat induces calcium deficiency in fetal and neonatal offspring,
who go on to be hypertensive, insulin resistant and have impaired glucose tolerance.
Calcium status in the adult strongly influences insulin sensitivity and secretion,
body composition and blood pressure, acting in part via increased blood calcitriol
and intracellular calcium levels in key tissues. We will therefore determine if
maternal calcium supplementation to ameliorate this placentally induced perinatal
hypocalcaemia, prevents the later onset of diabetes in offspring.
If efficacy is proven, this will provide the scientific evidence to justify
a follow-up study of the randomised clinical trial of maternal calcium supplementation
in pregnant women, examining the consequences for insulin action and glucose control
in offspring. Longer term, this will help determine if maternal calcium supplementation
is effective generally and in high-risk groups in particular, in reducing the
incidence of diabetes.
Funding:
National Health and Medical Research Council of Australia
Australian Diabetes Foundation
National Heart Foundation
Eli Lilly
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