Disorders of protein metabolism in the liver are central to the pathogenesis of diabetes and other disease states that affect nutrient homeostatis. Development of rational approaches to treatment of these disorders requires knowledge of the basic events involved in the regulation of hepatic protein metabolism. Therefore, the overall goal of this project is to provide a better understanding of the mechanisms by which hormones and nutrients regulate translational and transcriptional events in the protein synthetic pathway in liver. Studies of translational control are to focus on peptide-chain initiation using deficiency of single essential amino acids to induce an inhibition in formation of 40S initiation complexes, and diabetes to induce an inhibition subsequent to 40S initiation complex formation. Studies of transcriptional control are to focus on the mechanism of insulin action on gene transcription.
The specific aims of the studies are: (1) to investigate the mechanism of inhibition of peptide-chain initiation in livers deprived of single essential amino acids, particularly the role of eukaroytic initiation factor eIF-1; (2) to investigate the mechanism of inhibition of peptide-chain initiation in livers of diabetic animals, particularly the mount of mRNA and the role of initiation factors involved in mRNA binding; (3) to further characterize rat liver eIF-2, particularly with respect to its differences with the reticulocyte-derived factor; (4) to further purify and characterize the guanine nucleotide exchange factor from rat liver; and (5) to further define the actions of insulin on the relative abundance of mRNAs in primary cultures of rat hepatocytes. The studies are to eploy a number of experimental systems including the perfused liver, suspensions of isolated hepatocytes, primary cultures of hepatocytes, and a cell-free protein-synthesizing system derived from isolated hepatocytes. They are also to utilize a number of methodologies including protein purification, immunochemical identification and quantitation of proteins, one- and two-dimensional gel electrophoresis, quantitation of mRNAs by solution and dot-blot hybridization using specific cDNAs, ligand binding assays, protein kinase and phosphatase assays, and gene transcription assays. Overall, the studies desribed in this proposal should help identify mechanisms by which hormones and nutrients regulate protein synthesis. They should also provide new insights into biochemical events involved in peptide-chain initiation and gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK013499-25
Application #
2136791
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-05-01
Project End
1995-01-31
Budget Start
1993-05-01
Budget End
1995-01-31
Support Year
25
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Miller, William P; Mihailescu, Maria L; Yang, Chen et al. (2016) The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction. Invest Ophthalmol Vis Sci 57:1327-37
Dennis, Michael D; Kimball, Scot R; Fort, Patrice E et al. (2015) Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. J Biol Chem 290:3865-74
Kimball, Scot R; Ravi, Suhana; Gordon, Bradley S et al. (2015) Amino Acid-Induced Activation of mTORC1 in Rat Liver Is Attenuated by Short-Term Consumption of a High-Fat Diet. J Nutr 145:2496-502
Wang, Li; Liu, Xiaolei; Nie, Jia et al. (2015) ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology 61:486-96
Gordon, Bradley S; Kazi, Abid A; Coleman, Catherine S et al. (2014) RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells. Cell Signal 26:461-7
Fort, Patrice E; Losiewicz, Mandy K; Pennathur, Subramaniam et al. (2014) mTORC1-independent reduction of retinal protein synthesis in type 1 diabetes. Diabetes 63:3077-90
Dennis, Michael D; Coleman, Catherine S; Berg, Arthur et al. (2014) REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling. Sci Signal 7:ra68
Steiner, Jennifer L; Pruznak, Anne M; Deiter, Gina et al. (2014) Disruption of genes encoding eIF4E binding proteins-1 and -2 does not alter basal or sepsis-induced changes in skeletal muscle protein synthesis in male or female mice. PLoS One 9:e99582
Dennis, Michael D; McGhee, Nora K; Jefferson, Leonard S et al. (2013) Regulated in DNA damage and development 1 (REDD1) promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1 (mTORC1). Cell Signal 25:2709-16
Nie, Jia; Liu, Xiaolei; Lilley, Brendan N et al. (2013) SAD-A kinase controls islet ?-cell size and function as a mediator of mTORC1 signaling. Proc Natl Acad Sci U S A 110:13857-62

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