My research interests encompass genetic regulatory pathways that dynamically control developmental and physiological processes to adapt to internal or external perturbations. Currently, my research group is focused on regulation of metabolic and neurological processes that are particularly prone to maladaptations that lead to diseases such as diabetes, metabolic syndrome, and neurodegenerative diseases. We are investigating two key protein kinases, GCN2 and PERK, which phosphorylate the translation initiation factor eIF2 alpha. These kinases are dynamic sensors of physiological/developmental changes and act to modulate genetic networks for the purpose of adaptation. The importance of PERK was underscored by our finding that mice genetically deficient for PERK display permanent neonatal diabetes, exocrine pancreas atrophy, multiple skeletal dysplasias, severe metabolic dysfunctions, and growth retardation. The phenotype of the Perk knockout mouse parallels the human Wolcott-Rallison syndrome, also caused by Perk deficiency. Current research is focused in two areas: (1) regulation of insulin synthesis, quality control, and secretion in the pancreatic beta cell, and (2) regulation of neurological functions, particularly with respect to neurodegenerative disorders such as Alzheimer’s disease.
