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Jared Rutter

Assistant Professor of Biochemistry

B.S. Brigham Young University

Ph.D. University of Texas Southwestern Medical Center

Research

References

rutter@biochem.utah.edu

Jared Rutter's Lab Page

Jared Rutter's PubMed Literature Search

Research

My laboratory is interested in the reciprocal coupling of core metabolism and other cellular processes. Metabolic and nutrient status elicit substantial effects on a wide array of cellular biologies, including cell growth, cell division, protein synthesis and many others. Conversely, many cellular signaling pathways exert control on important metabolic decisions. Our broad goal is to begin to understand how this crosstalk occurs in normal situations and how its impairment is involved in disease states. Our present focus is on how the availability and quality of nutrients and energy effect cellular decisions, and how these cellular decisions then determine the use of available nutrients and energy (see Lindsley and Rutter, 2004). Our research currently centers in three areas: First, we are examining the regulation and function of PAS kinase, a protein we think participates in this system by sensing and signaling nutrient status. Second, we have started a new project to study the interplay between the mitochondria and the rest of the cell as it relates to metabolism and oxidative stress. Third, we are working to develop new technologies for the discovery of regulatory small molecule-protein interactions.

PAS kinase regulation: We have found that nutrient status regulates PAS kinase activity both in mammalian and yeast cells. Specifically, PAS kinase is activated in cultured beta-cells grown in elevated glucose (daSilva Xavier, et al. 2004), likely as a result of increased mitochondrial metabolism. Similarly, growth of yeast under conditions that require mitochondrial respiration (growth on non-fermentable carbon sources) also substantially activates PAS kinase (Grose, et al. 2007). We have also found that PAS kinase is an integral component of a system that maintains cell structural integrity (see below), and as such is activated by cell membrane stress (Grose, et al. 2007 and unpublished). Using both yeast and mammalian cells as model systems, we are trying to identify the factors that regulate PAS kinase, both transcriptionally and post-translationally.

PAS kinase and mammalian energy homeostasis: Diabetes mellitus is rapidly becoming one of the predominant health concerns of the western world. Fundamentally, diabetes is a failure of the insulin signaling system which functions to maintain blood glucose concentrations within a narrow range. A key component of this system is the pancreatic beta-cell which singularly has responsibility for insulin production and secretion in response to elevated serum glucose. We have found that PAS kinase is required for the synthesis of insulin in response to elevated glucose, at least in cultured beta-cells. We have extended these finding using mice wherein PAS kinase has been deleted (Pask-/- mice). These mice are hypoinsulinemic and as a result have an impaired ability to clear glucose after an injected glucose challenge. Further, isolated beta-cells from Pask-/- mice have a profound defect in glucose-stimulated insulin secretion in vitro. However, PASK-/- mice were resistant to high-fat diet induced obesity, hepatic steatosis and insulin resistance. This phenotype appears to be due to hypermetabolism in PASK-/- mice in vivo as measured by indirect calorimetry and in isolated skeletal muscle. These findings suggest an important physiological role of PASK in regulating metabolism and controlling energy balance in mammals (Hao, et al. 2007).

A major focus of our lab is to understand the mechanisms by which PASK controls both cellular and organismal energy metabolism. Specifically, we are working to understand how PAS kinase regulates mitochondrial metabolism in skeletal muscle (and probably in many cell types). We are also working to understand how PAS kinase controls hepatic lipid metabolism (as described in Hao, et al. 2007).

Mitochondria: It is increasingly apparent that mitochondria and their dysfunction lie at the heart of many human diseases. These include type 2 diabetes, a number of neurodegenerative disorders, cancer and aging itself. The understanding, prevention and treatment of these and other diseases requires a more complete understanding of how mitochondrial function, both in energy production and in cellular decisions, is regulated and maintained.

While much is known about mitochondria and their workings, much still awaits discovery. This is illustrated by proteomics experiments which show that more than 20% of mitochondrial proteins are essentially uncharacterized. This includes a large number that are highly conserved throughout eukarya, a strong indication that they perform a fundamental and important function. We have chosen to initiate studies to determine the genetic and biochemical function of eight of these conserved mitochondrial proteins. Each has been identified as mitochondrial, but has not been further studied. Of the eight, we have made substantial progress on understanding the function of two. The others are in various stages of progress. We are also working on parallel low resolution characterization of all yeast mitochondrial proteins.

 

References