|Objective of the European Nuclear Receptor Network|
|Diseases of lipid and glucose metabolism, such as cardiovascular
disease and type II diabetes, degrade the quality of life of several million
people within the European Union. There is mounting evidence to suggest
that a class of nuclear receptors play an important role in the regulation
of nutrient homeostasis. Recently, several of these nuclear receptors have
been implicated as causal factors in several of these illnesses. Nuclear
receptors are ligand activated transcription factors. It is thought that
these receptors regulate the expression of genes that encode key regulatory
components of metabolism.
The research objective of the network is to establish a multidisciplinary collaborative effort to the study a set of nuclear metabolite receptors in order to gain insight into their normal functions as well as their involvement in diseases. We propose to study these receptors by using a complex approach combining the efforts of five groups involved in different aspects of nuclear receptor research. By the combination of mouse genetics, preparative biochemistry, molecular and structural biology we hope to understand how these receptors regulate transcription in response to metabolites.
Our proposal includes studies on PPAR? a receptor implicated in fat cell differentiation, in the regulation of insulin sensitivity, in macrophage/foam cell differentiation and atherogenesis. This receptor will serve as a prototype for our studies. We also propose to study two less well characterized receptors : PPAR? and SXR. PPAR? is involved in catabolic processes of fatty acid metabolism whilst SXR is believed to be a steroid/xenobiotic sensor and regulates the expression of p450s. We believe that the successful completion of this project is likely to yield major advances in the fields of transcription biology, metabolic regulation and diseases.