Homeostatic responses to amino acid insufficiency
Alterations in amino acid availability and balance are sensed by overlapping signal transduction cascades. Two major signaling nodes responsive to amino acid supply in mammals are the: 1) Integrated Stress Response (ISR), also called the Amino Acid Response (AAR) and 2) mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway. While the mTORC1 pathway functions as a sensor of amino acid abundance to stimulate growth, the ISR/AAR is activated by amino acid deprivation to slow growth and instead favor cytoprotective and adaptive processes. How these signaling pathways work together to regulate gene-specific translation and promote cellular resilience is a major research focus of the lab. This project uses genetic strains of mice with targeted deficiencies in the ISR/AAR in combination of sophisticated molecular biology and stable isotope techniques to assess control of proteostasis and metabolism in tissues of mice.
Mechanisms of action and toxicity by asparaginase
Asparaginase is an important part of the remission induction regimen for treating acute lymphoblastic leukemia, the most common childhood cancer. The enzyme breaks down circulating asparagine and glutamine, creating a physiologically relevant model of amino acid deficiency. In leukemic cells which express very little asparagine synthetase (the enzyme that makes asparagine), asparaginase inflicts a lethal amino acid starvation. Yet for reasons not completely understood, cancer patients may unpredictably suffer severe complications, such as thromboembolism, liver failure and pancreatitis. Our lab was the first to report that phosphorylation of the translation factor, eIF2, by the amino acid sensor, GCN2, is activated by asparaginase. We were also the first to describe the ISR as the body’s first responder to asparaginase exposure. Since then we have gone on to show the impact of obesity and age on liver responses to asparaginase and we continue to use this agent as a research tool and study it to improve its efficacy to treat cancer and other diseases. This project utilizes a combination of biochemical, dietary, metabolic and molecular approaches in mice to identify mechanisms by which asparaginase causes metabolic complications and cell death. These results will be used to increase the safety and efficacy of asparaginase and to develop improved personalized approaches to the treatment of serious diseases.
ER stress and the Unfolded Protein Response
Chemical, environmental or nutritional perturbations that disrupt homeostasis within the endoplasmic reticulum (ER) activate a mechanism called the Unfolded Protein Response (UPR, also called the ER Stress Response). Phosphorylation of the translation factor eIF2 by PERK constitutes one arm of the UPR which serves to alleviate cell stress and re-establish homeostasis through a reprogramming of gene expression driven by the transcription factor ATF4. My laboratory is interested in exploring how the PERK-eIF2-ATF4 arm of the UPR contributes to the overall cellular effort to promote cellular adaptation and survival in response to a wide variety of environmental insults and proteotoxic stress agents.
Dietary protein, exercise, muscle growth and metabolic homeostasis
The interface of dietary protein and exercise as it relates to optimization of lean body mass is a longstanding area of interest and study. Previous projects in the lab include identifying metabolic and transcriptional signatures in the muscle of exercised horses, and varying the composition, distribution, source and/or timing of dietary protein on mTORC1 signaling and protein synthesis in mice. Information gained in this area will be targeted to relevant populations to improve performance and promote recovery and resilience.