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Nutritional programming of imprinted genes in the placenta

Reference	BB/C513626/1
Principal Investigator / Supervisor	Professor Abigail Fowden
Co-Investigators / Co-Supervisors	Professor Graham Burton, Dr Miguel Constancia
Institution	University of Cambridge
Department	Physiology Development and Neuroscience
Funding type	Research
Value (£)	332,917
Status	Completed
Type	Research Grant
Start date	01/10/2005
End date	31/03/2009
Duration	42 months

Abstract

Size at birth is critical in determining life expectancy. The smaller the neonate, the less likely it is to survive at birth and the more prone it is to adult-onset degenerative diseases. In mammals, the major determinant of intrauterine growth is the placental supply of nutrients to the fetus. In turn, this depends on the maternal nutritional state and the placental capacity to transfer nutrients to the fetus. These finding led to the concept that intrauterine tissue programming occurred during suboptimal nutritional conditions in utero. However, few studies have considered the contribution of the nutritional programming of the placenta per se to the aetiology of adult disease. Imprinted genes are important in placental development. They control the growth, morphology and nutrient transfer capacity of the placenta. In particular, the lgf2 H19 gene complex appears to have a major role in the structural and functional development of the murine placenta, altering the surface area and thickness of the barrier for nutrient exchange and the characteristics of the passive, facilitated and active transport processes. These genes also alter expression of the imprinted System A amino acid transporter gene, Slc38a4. Imprinted genes may, therefore, provide the genetic link between nutrition, intrauterine growth and the risk of adult disease. However, little is known about the nutritional regulation of these genes. The aim of this proposal is to identify the nutrient-gene interactions controlling placental phenotype, with particular emphasis on the imprinted genes, lgf2, H19 and Slc38a4. Using an integrated approach combining molecular biology, morphological analyses and physiological experimentation on the whole animal, the following four questions will be answered: Do natural variations in fetal nutrient availability produced by variations in litter size alter placental gene expression and phenotype? Do variations in maternal dietary composition and intake at critical stagesof placental development alter placental gene expression and phenotype? Does the placental specific Igf2 P0 transcript mediate the effects of nutrition on the placenta? Are the effects of nutrition on the placenta sex-linked? Placental size, morphology, gene expression (Igf2, H19 and Slc38a4 abundance and methylation) and nutrient transport (passive, facilitated and active transfer of radioactively labelled molecules) will be examined by sex (sex-linked effects) in mice on normal diets with varying litter sizes (natural constraint on nutrient availability), in mice on high fat, low protein or low calorie diets at critical stages of placental development (experimental dietary manipulation) and in mice carrying P0 mutants fed normal and altered diets (role of placental specific lgf2 transcripts). By establishing whether imprinted genes are modified epigenetically by nutrition, the study offers an unifying mechanism for the early life origins of adult disease via nutritional programming of the placenta. It also identifies critical periods in gestation when nutritional interventions may have life long health benefits.

Summary

unavailable

Committee	Closed Committee - Agri-food (AF)
Research Topics	Ageing, Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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