The incidences of adult cardiovascular and metabolic diseases are increasing worldwide at epidemic rates. Studies show that conditions of prenatal life, for instance the quality of maternal nutrition, relate strongly to the risk of such diseases. Tom Fleming’s work, using rodent models, has demonstrated that the earliest stage of embryo development, pre-implantation, is highly sensitive to maternal nutrient levels. Poor maternal protein nutrition can change the embryo’s development so as to increase its survival chances. This is called 'developmental plasticity', but it can ultimately lead to an increased risk of cardiovascular and metabolic disease in later adult life. New data on IVF children who may also have experienced relatively poor nutrient conditions as embryos in culture, show increased risk of elevated blood pressure and metabolic disorders. More recently, Tom Fleming’s research has focused on the mechanisms of embryo response to poor maternal diet and how these change the subsequent developmental programme. Discovering what induces developmental plasticity in embryos, would allow the devising of preventative strategies against adverse health outcomes.
Tom Fleming’s work indicates that the mother utilises the composition of amino acids and possibly insulin within the uterine lumen to communicate to the embryo that nutrient levels are poor which then provokes developmental plasticity. Using an embryo in vitro culture model developed to mimic conditions within the uterine lumen he will attempt to modulate this communication pathway and determine precisely the molecular configuration of amino acids and insulin that provoke embryo responses.
A second part of Professor Flemings study concerns the mechanism mediated by the mother in response to poor maternal diet. Preliminary data has shown that the uterine wall is induced to generate an increased supply of blood vessels in response to poor diet around the time of implantation. This discovery raises a new concept that the mother can enhance nutrient delivery in response to poor diet in early gestation. This maternal response will be characterised fully and assessed whether it is a direct response to dietary signals within the mother or induced through a signal mediated by the embryo. We will also assess, in quantitative terms, the contribution made by enhanced uterine vascularisation on embryo and fetal survival and growth relative to other aspects of embryo developmental plasticity.
These studies focus on the maternal mechanisms inducing potentially detrimental developmental programming in the embryo. They will provide a powerful resource for developing dietary/pharmacological strategies to combat adverse gestational induction of disease.
Funding duration: May 2011 - May 2014