The broad aim of my research program is to understand how the body senses and responds to changes in nutrient supply, and to more fully comprehend the cellular adaptive mechanisms triggered by environmental stress in the fight against chronic diseases such as cancer, diabetes and obesity. My primary research focus is to explore the cellular mechanisms triggered by altered amino acid availability delivered by diet, drug or genetic alteration and to understand how altering the supply of amino acids, in total or individually, regulates protein homeostasis in the whole animal. I am especially interested in the cellular sensing of amino acids and how affiliated signal transduction networks integrate with each other to regulate mRNA translation and DNA transcription in body tissues. I also have longstanding interests in metabolic and molecular responses to exercise. The research activities in my laboratory may be grouped into the following areas:
Homeostatic responses to amino acid insufficiency
Alterations in amino acid supply are sensed by overlapping signal transduction cascades. Two major signaling nodes responsive to amino acid supply are the 1) general amino acid control/amino acid response (AAR) pathway and the 2) mammalian target of rapamycin complex 1 (mTORC1) pathway. While the mTORC1 pathway is responsive to amino acid sufficiency and supplementation, the AAR is activated by amino acid insufficiency and deprivation. How these signaling pathways work together to maintain homeostasis by regulating gene-specific translation and subsequently gene expression is a major research focus of the lab. The objective of this project is to define the contribution of the AAR to the maintenance of protein balance during dietary restriction versus deprivation of amino acids. This project uses genetic strains of mice with targeted deficiencies in the AAR in combination of sophisticated molecular biology and stable isotope techniques to assess control of protein synthesis and protein degradation in the liver and skeletal muscle of mice.
Mechanisms of 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. Because leukemic cells express very little asparagine synthetase (the enzyme that makes asparagine), the tumor suffers a lethal amino acid starvation. Yet for reasons not well understood, cancer patients may unpredictably suffer severe complications, such as thromboembolism, liver failure and pancreatitis. This project utilizes a combination of biochemical, dietary, metabolic and molecular approaches in mice to identify mechanisms by which asparaginase causes metabolic complications. These results will be used to increase the safety and efficacy of asparaginase and to develop improved personalized approaches to chemotherapy.
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 stressors.
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. Current 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 can influence signaling pathways that regulate tissue growth and development. Information gained in this area will be used to create novel approaches to better prevent and treat chronic disease and promote longevity.