Dept. of Nutritional Sciences
School of Env & Biol Sciences
Institute for Food, Nutrition & Health
61 Dudley Rd
New Brunswick, NJ 08901-0231
Protein and amino acid metabolism; adaptation to cell stress by eIF2 and mTOR pathways; nutrition and exercise
Cellular stress responses to amino acid deprivation
My laboratory explores the cellular mechanisms triggered by nutrition stress, particularly the signaling and gene expression pathways activated by amino acid deprivation. Two major signaling nodes responsive to amino acid deprivation are namely, eukaryotic initiation factor 2 (eIF2) and mammalian target of rapamycin (mTOR). Both of these control points are regulated by phosphorylation and both proteins influence how the cell responds to changes in amino acid supply.
In eukaryotes, phosphorylation of eIF2 is triggered by a family of four protein kinases. This phosphorylation event serves to dampen protein synthesis to preserve energy but also to reconfigure gene expression to promote adaptation and cell survival. In conditions of irremediable stress, gene expression switches toward programmed cell death pathways in order to limit tissue or organ damage. How this signaling pathway switches from cell survival and adaptation toward apoptosis is an area of active study. In this regard, my laboratory examines how the eIF2 kinases named GCN2 and PERK influence adaptation to amino acid stress produced by the anti-cancer drug asparaginase. Asparaginase is an integral part of the treatment for acute lymphoblastic leukemia, the most common childhood cancer. Asparaginase produces immunosuppression, pancreatitis, and hepatotoxicity with related metabolic complications that include fatty liver, reduced plasma proteins, and coagulation problems that lead to thromboembolism and cerebrovascular events. Studies currently ongoing are purposed toward identifying key molecular events in the eIF2 and mTOR signaling pathways that modulate hepatic dysfunction by asparaginase. These results will be used to increase the safety and efficacy of asparaginase and to develop and test improved methods of treatment.
ER Stress and the Unfolded Protein Response
Chemical or environmental perturbations that disrupt the folding capacity of the endoplasmic reticulum (ER) activate a tripartite mechanism called the Unfolded Protein Response (UPR, also called the ER Stress Response). Phosphorylation of eIF2 by PERK constitutes one arm of the UPR which serves to alleviate cell stress through a reprogramming of gene expression driven by increases in the synthesis of the transcription factor ATF4. My laboratory is interested in exploring how the PERK-eIF2-ATF4 arm of the UPR contributes to the overall efficacy of the UPR in response to a wide variety of environmental stressors.
Dietary Protein, Muscle Growth and Metabolic Homeostasis
The interface of dietary protein and exercise as it relates to weight control and optimization of lean body mass is a longstanding area of interest and study. In particular, my lab is interested in how varying the composition, distribution, source and/or timing of dietary protein can influence signaling pathways that regulate tissue growth and development. Aside from the eIF2 signaling pathway, the mTOR complex 1 (mTORC1) signaling pathway is a major transducer of cellular information regulating both protein synthesis and protein degradation processes in response to four major signal inputs: nutrients (i.e., amino acids), growth factors, energy and stress. Information gained in this area will be used to create novel approaches to better prevent and treat diabetes and obesity.