Elucidating the role of endogenously produced inhibitors of nitric oxide synthesis in nutrient sensing and cellular hypertrophy.

Endogenously produced inhibitors of nitric oxide synthesis (Asymmetric dimethylarginine, ADMA) have been implicated in the physiological and pathophysiological regulation of nitric oxide in experimental animals and humans (Leiper and Nandi 2011, Nat Rev Drug Discov 10, 277). Elevation of the concentration of ADMA attenuates vascular nitric oxide signaling resulting in a number of phenotypes including reduced angiogenesis and hypertension(Leiper et al. 2007, Nat Med 13, 198). In lipogenic tissues, elevation of ADMA induces lipid synthesis and cellular hypertrophy that leads to increased body fat mass. The mechanisms underlying these effects on lipogenic tissues are not completely understood but are independent of nitric oxide synthesis. Recently we have identified a receptor mediated signaling pathway for ADMA that contributes to cellular hypertrophy. The aims of this project are to elucidate the components of this signaling cascade at the molecular level, identify additional tissues in which nitric oxide-independent ADMA signaling operates and to determine the contribution of nitric oxide-independent ADMA signaling to pathology in experimental models of disease such as diabetes and obesity. To achieve these goals will utilise a wide range of molecular and cell biological techniques and take advantage of model organisms such as Drosophilla and mice with the ultimate aim of translation into humans.