David Ron M.D.
Professor of Cellular Pathophysiology and Clinical Biochemistry
and Wellcome Trust Principal Research Fellow
Research Interests: Protein misfolding and metabolic disorders
Proteins that fail to attain or maintain their structure reduce fitness in part through toxic gain of function mechanisms referred to as "proteotoxicity". The latter conspicuously affects poorly-renewable tissues of long-lived organisms in which the threat of protein misfolding can exert its deleterious consequences over extended periods of time. Protein misfolding is compartment-specific and its extent is influenced by the burden of newly-synthesized unfolded proteins presented to given compartment (cytosol, endoplasmic reticulum, mitochondria) and by the protein folding environment in that compartment. The latter is influenced by structural elements operating within and on the compartment and by its metabolic state. Both parameters are regulated by complex homeostatic pathways, constituting what has been termed heuristically a proteostasis network in which compartment-specific unfolded protein responses (UPR) are important.
Interesting reciprocal links have been uncovered between protein folding homeostasis and metabolism: Defects in handling unfolded protein load and proteotoxic features of rare mutant proteins have revealed the importance of proteostasis to the function of tissues such as the endocrine pancreas, liver and fat that figure heavily in metabolic control. Less well understood, but of potentially considerable importance, are the emerging links between intermediary metabolism and the protein folding environment in the various compartments of the eukaryotic cell. Working with colleagues at the Metabolic Research Laboratories of the Institute of Metabolic Science, we hope to understand the molecular basis of the aforementioned reciprocal links and thereby uncover informative clinical markers and targets for future therapeutic interventions.