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Dr Amanda Sferruzzi-Perri
NHMRC Overseas Biomedical Research Fellow
| Discipline |
Physiology, Development and Neuroscience |
| Address |
Centre for Trophoblast Research, University of Cambridge |
| Telephone |
+44 (0) 1223 333 863 |
| Facsimile |
+44 (0) 1223 333 840 |
| Email |
ans48@cam.ac.uk |
My research focuses on the control of intrauterine growth and development of the placenta, the organ responsible for supplying the fetus with nutrients for growth. Poor placental development affects 20% of pregnant Australian women, increasing maternal and fetal rates of mortality and morbidity. Impaired fetal growth resulting from placental insufficiency also increases the risk of adult onset degenerative diseases that shorten lifespan, such as hypertension, obesity and diabetes. The aims of my research are, therefore, to identify the causes and potential therapeutic treatment of poor placentation. I have been characterising the genetic and endocrine mechanisms controlling feto-placental development with particular emphasis on two naturally occurring hormones, insulin-like growth factors (IGF) I and II. My PhD research undertaken at the Research Centre for Reproduction Health at the University of Adelaide showed using human placental tissue and animal models, that these two IGFs act through different, though complementary mechanisms to stimulate fetal growth. In particular, maternal IGF-II, promotes differentiation of the placental region responsible for materno-feto exchange, increasing nutrient transport. Through the award of an NHMRC Overseas Biomedical Fellowship, I have now moved to the UK to work in the recently established Centre for Trophoblast Research at the University of Cambridge to identify the molecular mechanisms by which IGF-II acts on placental development with particular reference to the intracellular ‘nutrient sensor’, mTOR (mammalian target of rapamycin). Since arriving in Cambridge a year ago, I have shown that the placental Igf2 gene has a pivotal role in the adaptive responses of the placenta to maternal undernutrition (Reprod Sci 16:165A). Now, I am investigating whether this gene mediates the placental responses to altered dietary fat and protein content and the extent to which IGF-II administration can alleviate the adverse placental consequences of maternal dietary manipulations. This work utilises an integrated approach combining in vivo animal experimentation with cellular and molecular analyses and in collaboration with Prof Graham Burton, Prof Abigail Fowden and Dr Miguel Constancia.
Collaborators:
- Prof Graham Burton (Centre for Trophoblast Research, University of Cambridge)
- Prof Abigail Fowden (Centre for Trophoblast Research, University Cambridge)
- Dr Miguel Constancia
- Prof Anne Ferguson-Smith (Department of Physiology, Development and Neuroscience, University of Cambridge)
- Dr Francesco Colucci (Babraham Institute, Cambridge)
- A/Prof Claire Roberts (Research Centre for Reproductive Health, University of Adelaide)
- A/Prof Sarah Robertson (Research Centre for Reproductive Health, University of Adelaide)
Current projects:
The role of nutrition and IGF-II in programming placental development and function, and thus fetal growth. (Fellowship)
Collaborators: Professors Fowden and Burton and Dr Constancia, University of Cambridge.
So far, this work has implied that the placental specific transcript of the Igf2 gene is pivotal in placental adaptation to maternal undernutrition and thus the regulation of fetal growth. However, the molecular mechanisms that transduce the effect of nutrition and IGF-II in the placenta are unknown. Present evidence from the laboratory suggests that signalling down the growth regulating protein kinase B (AKT) pathway are altered in response to undernutrition leading to impaired placental development. Further investigations are currently underway to better define these pathways.
The effect of a high sugar and fat (HSHF) maternal diet on placental morphogenesis, metabolism and nutrient transport and fetal growth. (Fellowship)
Collaborators: Professors Fowden and Burton, University of Cambridge.
So far, this work has shown that feeding a mother a HSHF diet during pregnancy reduced placental growth and amino acid transport without affecting fetal growth near term. This suggests that other compensatory mechanisms must, therefore, exist to account for the increased efficiency of the small HSHF placenta. The impact of HSHF diets on other placental nutrient transfer systems and maternal metabolic profiles, are currently being investigated.
The role of the retrotransposon gene, Rtl1 in placental development and function and fetal growth.
Collaborators: Professor Ferguson-Smith and Dr Ito, University of Cambridge.
These studies have suggested that RTL1 is a critical determinant of placental vasculogenesis and morphogenesis of the exchange region, and hence fetal growth. Furthermore, this gene is regulated by the expression of a microRNA which is imprinted, providing novel insights into the regulation of placental development.
The role of uterine natural killer cells (uNK) in placental perfusion and morphogenesis and fetal growth.
Collaborators: Dr Colucci, Babraham Institute and Prof Burton and Dr Yung, University of Cambridge.
These studies have revealed that a deficiency in maternal uNK cells in the endometrium leads to reduced maternal blood flow into the developing placenta, reducing activity in intracellular growth signaling (presumably through increased placental oxidative) and perturbs placental morphogenesis and fetal growth.
Placental development and function in response to maternal glucocorticod treatment.
Collaborator: Prof Fowden and Mr Vaughan, University of Cambridge.
This study is investigating the morphology and function of the growth retarded placenta induced by maternal administration with synthetic glucocorticoid commonly used to treat women threatened with preterm delivery. So far, this work has showed that the small synthetic glucocorticoid treated placenta upregulates amino acid transport.
The roles and interactions of IGF-II and oxygen in early human placental development in vitro.
Collaborator: A/Prof Roberts, Research Centre for Reproductive Health, University of Adelaide.
This work demonstrated that placental synthesis of IGF-II in early pregnancy is responsive to oxygen availability and mediates the effect oxygen via novel interactions with other growth factors at the feto-maternal interface. Furthermore investigations are currently underway in the Roberts laboratory to characterise these pathways in placental trophoblast, proliferation invasion and migration in vitro.
Recent Publications
REVIEW PAPERS
Fowden AL, Sferruzzi-Perri AN, Coan PM, Constancia M, Burton GJ (2009) Placental efficiency and adaptation: endocrine regulation. Invited Review, Journal of Physiology, JPHYSIOL/2009/173013 In press
Pringle, KG, Kind KL, Sferruzzi-Perri AN, Thompson J, Roberts CT (2009) Beyond Oxygen: Complex Regulation and Activity of HIFs in Pregnancy. Human Reproduction Update, Accepted with revisions HRU-09-0006
Roberts CT, Owens JA, Sferruzzi-Perri AN (2007) Distinct actions of insulin-like growth factors (IGFs) on placental development and fetal growth. Placenta 29 Suppl A:S42-7.
Roberts CT, Sferruzzi-Perri AN, Kind KL, Robinson JS and Owens JA (2005) Placental perturbations and pregnancy outcome: a common thread*. Workshop on Comparative Placentology Havemeyer Foundation Monograph Series17:54-56. Available online: http://havemeyerfoundation.org/monograph.htm
*Highly specialised publication
PEER-REVIEWED MANUSCRIPTS
Sferruzzi-Perri AN, Macpherson AM, Roberts CT, Robertson SA (2009) GM-CSF regulates trophoblast glycogen cell and giant cell differentiation in placental morphogenesis. Biology of Reproduction In press BIOLREPROD/2008/073312, available online PMID: 19228596
Sferruzzi-Perri AN, Owens JA, Standen P, Roberts CT (2008) Maternal insulin-like growth factor-II promotes placental functional development and fetal growth via the type 2 IGF receptor in guinea pigs. Placenta 29:347-55
Sferruzzi-Perri AN, Owens JA, Standen P, Taylor RL, Robinson JS, Roberts CT (2007) Early pregnancy maternal endocrine IGF-I programs the placenta for increased functional capacity throughout gestation. Endocrinology 148(9):4362-70.
Sferruzzi-Perri AN, Owens JA, Standen P, Taylor RL, Heinemann GK, Robinson JS, Roberts CT (2006) Early treatment of the pregnant guinea pig with IGFs promotes placental transport and nutrient partitioning near term. American Journal of Physiology, Endocrinology and Metabolism 292: E668-E676.
Sferruzzi-Perri AN, Owens JA, Pringle KG, Robinson JS, Roberts CT (2006) Maternal insulin-like growth factor-I and –II act via different pathways to promote fetal growth. Endocrinology 147(7):3344-3355.
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