The role of amino acid status as a signaling event and the pathway by which it signals resulting in ? cell apoptosis has not been evaluated as a causative event. Beyond the consequences of hyperglycemia and hyperlipidemia, additional molecular mechanism (s) that cause ? cell apoptosis during development of diabetes are not well studied but will be vital for the development of novel diagnostic and therapeutic strategies. Apoptosis of ? cells in Type 2 Diabetes (T2DM) is associated with increased stress in the endoplasmic reticulum (ER). Our laboratory has contributed a body of work on the cellular responses to diverse stress conditions, including ER stress and amino acid limitation. Combined work from many labs has shown that the cellular response to ER stress involves the translation and transcriptional reprogramming of cells. We discovered a novel anabolic program that accompanies the translational recovery of late ER stress. This program promotes amino acid uptake, increased tRNA charging, and increased expression of genes involved in protein synthesis. This program which has prosurvival and growth actions under mild stress, paradoxically, promote apoptosis under conditions of chronic stress, by stimulating protein synthesis, by inducing the production of reactive oxygen species, and by exhausting the ATP supply. We propose to study the molecular mechanism of this novel 'suicide'adaptive stress response in insulinoma cells and islets from diabetic mouse models. We will study (i) the mechanisms of transcriptional and translational control, (ii) the mechanism and significance of increased amino acid uptake in the regulation of mRNA translation and (iii) the mechanism via which increased methionine and cystine uptake contribute to protection of ? cells from ER stress-induced apoptosis. Our studies will reveal novel biomarkers in ER stress-induced diabetes (a condition related to T2DM), with diagnostic and therapeutic potential.

Public Health Relevance

Anabolic cellular responses are associated with growth, proliferation and increased metabolic activity. They are usually observed in tumor cells. We made the unexpected finding that insulin-producing pancreatic ? cells induce an anabolic gene expression program in response to stress in the endoplasmic reticulum (ER). ER stress in ? cells is associated with ? cell apoptosis in Type 2 Diabetes (T2DM), an important feature of the disease. In this proposal we will study the components of this anabolic program that lead to apoptosis of ? cells. We aim to discover novel biomarkers for diagnosis and treatment of T2DM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053307-16A1
Application #
8578288
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
1998-01-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
16
Fiscal Year
2013
Total Cost
$549,529
Indirect Cost
$196,830
Name
Case Western Reserve University
Department
Nutrition
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Guan, Bo-Jhih; Krokowski, Dawid; Majumder, Mithu et al. (2014) Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2?. J Biol Chem 289:12593-611
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Han, Jaeseok; Back, Sung Hoon; Hur, Junguk et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15:481-90
Majumder, Mithu; Huang, Charlie; Snider, Martin D et al. (2012) A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. Mol Cell Biol 32:992-1003
Mounir, Zineb; Krishnamoorthy, Jothi Latha; Wang, Shuo et al. (2011) Akt determines cell fate through inhibition of the PERK-eIF2? phosphorylation pathway. Sci Signal 4:ra62
Komar, Anton A; Hatzoglou, Maria (2011) Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle 10:229-40
Basu, Abhijit; Das, Priyanka; Chaudhuri, Sujan et al. (2011) Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites. Mol Cell Biol 31:4482-99
Krokowski, Dawid; Gaccioli, Francesca; Majumder, Mithu et al. (2011) Characterization of hibernating ribosomes in mammalian cells. Cell Cycle 10:2691-702
Hsieh, Chang-Wen; Huang, Charles; Bederman, Ilya et al. (2011) Function of phosphoenolpyruvate carboxykinase in mammary gland epithelial cells. J Lipid Res 52:1352-62

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