Modulation of intracellular energy balance-controlling signalling pathways in therapy of cancer and neuro-immuno-endocrine disorders

Disruption of intracellular energy balance is a common feature of cancer and various metabolic, neurological and immune disorders. Adenosine monophosphate-activated protein kinase (AMPK) is a key intracellular energy sensor that preserves energy by modulating the activity of metabolic enzymes and signalling molecules (Raptor, Akt, mTOR, p70S6K, 4E-BP1) involved in regulation of protein synthesis and proliferation. The proposed translational research will assess therapeutic potential of modulating energy-sensing signalling pathways in experimental models of cancer and neuro-immuno-endocrine disorders. The AMPK expression/activity in relevant cell types (cancer cells, CNS cells, immune cells, endocrine cells) will be modulated in vitro genetically or pharmacologically. Cell proliferation, immune function, metabolic status, damage and death, as well as their mutual relationships, will be assessed using appropriate state-of-the-art methods of cellular and molecular biology. The therapeutic potential of pharmacological AMPK modulation will be explored using in vivo experimental models of cancer, neurodegeneration, inflammation/autoimmunity and energy balance disorders, as well as by analyzing the AMPK signalling in relevant clinical samples and correlating its activity with markers of disease progression. Such an approach should provide grounds for targeted modulation of energy-sensing signalling in future clinical trials.