Research interests: gene regulation, protein biogenesis and secretion, metabolic and neurological diseases, cancer biology, ER stress and the unfolded protein response.
Metabolic and neurological diseases
We are interested in how key regulators of protein synthesis and trafficking control cell proliferation and secretion of hormones that control metabolic and neurological functions. Through mutational analyses of the mouse model of the human Wolcott Rallison Syndrome, we discovered that the PERK eIF2a kinase is responsible for regulating cell growth and secretory functions in several organs throughout the body. Of particular interest to our current research, we found that PERK is required for both the proliferation of the insulin-secreting beta cells of the pancreas and the trafficking, quality control and secretion of insulin.
Currently we are investigating two questions related to PERK’s function in the pancreatic beta cell. (1) What is the metabolic function of PERK in regulating beta cell proliferation and insulin secretion? Our current hypothesis is that PERK acts as metabolic sensor for changes in nutritional status and then in turn modulates gene expression to increase or decrease the synthesis and secretion of insulin. (2) What are the downstream targets of PERK dependent regulation? We speculate that PERK is specifically controlling the expression of transcription factors that regulate beta cell proliferation and insulin biogenesis and secretion.
We use a combination of genetic, molecular, and cellular techniques in our studies and have developed a unique set of genetic strains to probe the tissue-specific functions of PERK. These studies are of great interest to understanding the cause and cure for diabetes and the connection between of obesity and diabetes.
The role of PERK in regulating important functions in the brain has become a hot topic of interest as related to learning and memory, regulation of stress responses, and to neurological diseases including Alzheimer’s and the autism spectrum/Schizophrenia complex of related disorders. Using our unique mouse genetic strains, we have developed brain specific PERK knockout mice to investigate the function of PERK in controlling protein synthesis and secretion of neuronal tissue in the context of these neurological diseases.
Cancer growth and development
Tumor growth is controlled both by intrinsic regulatory factors within tumor cells and by the extrinsic environment including that supports or inhibits it growth. Recent studies by our group and others have shown that PERK is required for rapid tumor growth and angiogenesis. We are currently conducting studies to determine if PERK dependent tumorgenesis resides in both the tumor cells and adjacent vascular tissue that feeds the growth and development of tumor. Tumor-specific and endothelial-specific PERK KO mice are being used to address these questions and to also identify the downstream molecular targets of PERK regulation. In addition, we are testing the ability of PERK-specific enzyme inhibitors to repress cancer in mouse models in collaboration with GlaxoSmithKline.
ER stress and the unfolded protein response
Studies in cultured mammalian cells have revealed a stress response pathway that is activated by protein misfolding in the endoplasmic reticulum or perturbations in calcium homeostasis. PERK, IRE1, and ATF6 are the key sensors of the ER stress response and their activation results in repression of global protein synthesis and induction of genes encoding a select group of ER chaperones and ERAD (ER associated protein degradation) proteins. Because the discovery of these stress related functions predated the discovery of the normal (non-stress) functions of PERK, IRE1, and ATF6 it is commonly assumed that the normal functions of these proteins are simple extensions of their stress regulatory functions. However, our detailed genetic studies of PERK have clearly shown that its normal developmental and physiological functions are distinctly different than it stress related functions. Our research is attempting to understand how the normal functions of the PERK are co-opted during ER stress to regulate different pathways. In addition, we have found that the unfolded protein/ER stress response is quite different in complex multicellular organisms than what has been reported in cell culture. Because of the enormous interest in the role that ER stress may play in human disease, it is essential that we understand the ER stress response in whole organisms.