The fetal origins of adult disease hypothesis proposes that late onsetdisorders such as heart disease and type 2 diabetes maybe a consequenceof metabolic programming in response to poor nutrition in utero.Accordingly, it has been suggested that the baby receives from theirmother a forecast of the nutritional environment they will receiveafter birth and modify its metabolism, whole body physiology and growthtrajectory appropriately to maximize its chances of survivalpostnatally. However, these adaptations become detrimental if thepostnatal conditions differ from those experienced during fetal lifeand thus lead to increased disease susceptibility. This hypothesis hasbeen supported by numerous epidemiological studies, which have shown anassociation between low birth weight and the subsequent development oftype 2 diabetes, insulin resistance and the metabolic syndrome, andalso by a number of animal studies. However, very few studies haveaddressed the molecular mechanisms by which a phenomenon that occurs inutero has a phenotypic consequence many years later. This studentshipwill aim at providing first experimental evidence that epigeneticsplays an important role in this fascinating biological phenomena.Epigenetics refers to covalent modifications of DNA and core histoneswhich are heritable and affect genome function without altering thenucleotide sequence of DNA. It is an attractive candidate mechanism forfetal programming because it confers and maintains cellular "memory"for many cell divisions. The student will use an integrated approachcombining whole animal nutritional programming, gene-specific candidateapproaches and functional epigenomics using DNA arrays to detectalterations in the epigenome associated with nutritional programming.These studies will be performed on a defined cell type of keyimportance in the pathogenesis of type 2 diabetes, the pancreatic betacell, in the well established maternal protein restriction animal modelof fetal programming. Subsequent work will focus on targeting DNAmethylation to key metabolic genes to induce gene expression andmetabolic changes in vitro. This studentship may lead to theidentification of novel causes and biomarkers of type 2 diabetes (adisease that affects 150 million worldwide). This work is done in closecollaboration with the fetal programming group of Dr. Susan Ozanne atthe Department of Clinical Biochemistry, University of Cambridge.

Contact:
Dr Miguel Constancia
Email: Miguel.constancia@bbsrc.ac.uk
Tel: 01223 496496