Metabolic Signalling

Current research projects

• mTORC1-AMPK signalling

  AMPK is a serine/threonine protein kinase with central roles in cellular metabolism. AMPK acts as a node for multiple signalling inputs (e.g. phosphorylation, ubiquitination), however understanding of the functional and biological consequences of these modifications is very limited. Expanding on our recent discovery that AMPK is a direct substrate for the mTORC1 kinase, this exciting project will discover new aspects of AMPK regulation that may underpin new treatments for cancer. See Ling et al, Nature Metabolism 2(1):41-49 (2020).

  AMPK drug discovery 1 – small molecule activators

  The metabolic dimensions of type 2 diabetes (T2D), cardiovascular disease, obesity and cancer have driven efforts to progress pharmacological modulators of AMPK to the clinic. Activation of AMPK in skeletal muscle improves glucose control and surgery outcomes in patients with T2D, and could potentially reverse insulin resistance to prevent disease pathogenesis. Working with medicinal chemists at MIPS, this project will drive the development of drugs that specifically activate AMPK isoforms found in skeletal muscle, thereby avoiding adverse effects associated with systemic activators. See Ovens et al, Biochemical Journal 479(11):1181–1204 (2022).

  AMPK drug discovery 2 - small molecule inhibitors

  AMPK becomes hyperactive in a wide range of prevalent human diseases and conditions, including ischemic stroke, neurodegeneration, cancer and viral infection. In ischemic stroke, a life-threatening or debilitating event for many millions worldwide with no immediate therapeutic options, AMPK activation has been linked to excitotoxic shock that damages neurones surrounding the initial ischemic core. We are in a unique position to explore pharmacological AMPK inhibition as a strategy to reduce neuronal damage associated with ischemic stroke. Using cutting-edge phosphoproteomics and inducible mouse models of stroke, this project, supported by the SVI Discovery Fund, will assist in providing proof-of-concept on inhibiting AMPK in the brain to improve patient outcomes and rehabilitation, ultimately leading to a reduction in disease burden for people affected by stroke and their carers. See Hoque et al, Cell Death & Disease 10(3):213 (2019); Dite et al, Journal of Biological Chemistry 293(23):8874–8885 (2018).

  Metabolite regulation of mitochondrial health

  Mitochondria, the powerhouses of the cell, are organelles that provide cells with the essential chemical energy they need for almost all biochemical processes. The mitochondrial network is maintained by a precise equilibrium between fission and fusion events, dysregulation of which leads to poor mitochondrial health associated with many diseases. Our recent discoveries of how the enzyme DRP1 – the effector of mitochondrial fission and a direct AMPK substrate – is directly regulated by lipids opens up exciting avenues for research into DRP1 biology and the effects of obesity on mitochondria. See Rosdah et al, Pharmacology and Therapeutics, 213:107594 (2020).