Illuminating the biology of the GPR101 receptor: analysis of its transcriptional regulation and validation of new ligands

X-linked acrogigantism (X-LAG) is an extremely rare and severe form of gigantism. The excessive body growth begins during infancy and is caused by enhanced production of growth hormone from the pituitary gland. This pathology is associated with a genetic defect: duplication of the GPR101 gene. GPR101 specifies for a receptor localized in the outer layer of cells. The expression and activity of the GPR101 receptor is strongly enhanced in the pituitary tumors of X-LAG patients. However, we still know little about how GPR101 expression is controlled in the pituitary gland. The objectives of this research project are to identify a) the molecular mechanisms that cause the marked expression of GPR101, and 2) specific inhibitors of its activity. To attain objective 1, I will study DNA sequences called enhancers. Enhancers promote gene expression, acting like a “turbo”. Thanks to innovative techniques, I will investigate whether in X-LAG patients the GPR101 gene displays aberrant interactions with enhancers active in the pituitary gland. To attain objective 2, I will test the efficacy of candidate GPR101 inhibitors that I have recently identified. I will carry out these experiments in animal cells that strongly express GPR101, mimicking what happens in the human disease. Unraveling the pathological mechanisms controlling GPR101 expression allows to significantly expand our understanding of X-LAG etiology. Identifying drugs that shut down an overactive GPR101 represents the first step towards the development of a specific treatment for X-LAG. Studying all these aspects could also benefit patients affected by other growth and pituitary disturbances.