Genomic Imprinting and the regulation of postnatal nutritional resources via breastmilk

The control of nutritional from mother to her baby is essential for the lifelong health and wellbeing of offspring. Our proposal aims to understand key mechanisms that regulate successful breastfeeding; in particular the normal production of breastmilk and the processes ensuring that its content is optimum for supporting the baby.
We study a particular set of genes called 'imprinted genes' that are known to be important for regulating prenatal growth of the baby and its placenta. Evidence from ourselves and others has suggested that these genes also regulate important processes after birth, including breastfeeding, but very little is known about the function of imprinted genes in postnatal nutritional control.

Our first aim is designed to address the extent to which the protein products from imprinted genes can be found in breastmilk, both in the first fluid consumed by the baby after it is born, and in later milk once it is a little older. We will quantify these proteins in milk over time. This is important first step in understanding if imprinting as a process can help babies grow properly, and may have implications for lifelong health and for babies failing to thrive.

In our second aim, we will apply our current knowledge on the cells in the mammary gland which are responsible for milk production and study the developmental changes occurring in these specific cell types of the mammary gland during pregnancy and lactation. This will contribute to our understanding of the production of milk proteins. This more detailed analysis on the regulation of imprinted gene products might also provide useful fundamental insights into the function and evolution of the imprinting process.

Our third aim is to study the importance of the protein products of imprinted genes to the successful growth and development of the offspring. We will check how the presence of these protein products affect normal and abnormal growth of new-borns, and if they have any long-term effect on their life-long health for example on their risk to develop diseases such as obesity and diabetes which are known to be reduced by breastfeeding.

The main goal of this programme is to understand the importance of imprinted proteins in the milk, how they regulate growth and development beyond the womb, and the influence of this aspect of nutritional control on the early origins of health and disease.

Genomic imprinting is an epigenetic process causing genes to be expressed monoallelically according to their parental origin. It is well established that imprinted genes have major prenatal effects on growth, development and placental physiology. Recent evidence suggests that imprinted genes play important roles postnatally as well. In human, defective imprinting causes a series of congenital diseases with overlapping clinical features including abnormal growth and metabolism and is associated with obesity, diabetes and cancer. Epidemiological studies indicate that some of these diseases are also associated with early postnatal nutrition; specifically, that breastfeeding is protective against early postnatal morbidity and is also beneficial against obesity, diabetes and cancer. Yet, the mechanisms underlying the links between early nutrition and the origins of health and disease remain unknown.

Based on our preliminary data, we hypothesise that imprinting, also extends to postnatal nutritional control via the milk and that imprinting products secreted into the milk are transferred to the offspring and modulate growth, development and metabolism.

We propose a series of experiments addressing key biomedically relevant topics concerning the presence, origin and function of imprinted proteins in milk. These studies are designed not only to better understand mechanisms of early nutrition, but also to provide major insights into the physiological significance, function and evolution of genomic imprinting.
We aim to:
1 - To quantify and characterise imprinted proteins and their temporal dynamic in mammalian milk over lactation.
2 - To associate the presence of imprinting proteins with normal mammary cell transcriptomes and explore the relationship between them and milk RNA.
3 - To study the physiological significance of imprinted proteins in milk using the mouse as a model, how do they affect the offspring's growth, development and long-term health.