Understanding ATM dependent control of cellular metabolism

Ataxia-Telangiectasia or A-T, is a rare and complex monogenic disorder. It is often referred to as a 'multi-system' disorder because it affects a number of different systems within the body. Amongst the most significant signs of the disease there are: a) increasing difficulty in coordinating movements (ataxia); b) an increased risk in developing cancers; c) reduced efficiency of the immune system leading to more frequent infections (immunodeficiency); d) increased sensitivity to x-rays; e) prominent blood vessels often in or around the eyes (telangiectasia). A-T is caused by a mutation on the ATM gene, which plays an important role in many cell functions and when it is absent or not working as it should, this gives rise to the wide range of symptoms of A-T. Understanding how ATM works will help designing therapeutic strategies to treat AT. This research will also benefit a number of genetic diseases that share some of the symptoms common to A-T. Our preliminary results and published evidence highlighted the presence of significant metabolic imbalances in A-T cells. Here we propose to characterize these metabolic imbalances, to understand their molecular and physiological causes, and to restore normal metabolism in A-T cells. In particular we will focus our studies on metabolic imbalances that could be tackled with existing drugs and compounds already used in the clinic.