Proteostasis is achieved by a cellular network that coordinates protein synthesis, folding and degradation. Aging, transient fluctuations or persistent exposure to environmental or intracellular perturbants of proteostasis can lead to onset of disease, such as neurodegeneration and diabetes. Proteostasis during stress is largely maintained by adaptations in cellular capacity for protein synthesis and folding, thus avoiding the accumulation of damaged proteins that may result in deleterious effects on cell fate. Specifically, the Unfolded Protein Response (UPR) is a stress response that can rapidly change the capacity of the proteostasis network. However, there is a knowledge gap on the stress sensing and adaptation mechanisms during persistent UPR, before development of disease. We propose that the adaptive UPR during persistent stress exposure comprises the coordinated action of transcriptional, translational and metabolic reprogramming that maintains essential cellular functions and stress sensing while preventing cell death caused by ER dysfunction. We propose (i) Characterize a novel mechanism of adaptation to chronic stress using physiologically relevant models of persistent ER stress induction in pancreatic ? cells. (ii) Determine the molecular mechanism of proinsulin mRNA translation in pancreatic ? cells during persistent ER stress and (iii) Characterize a novel adaptive mechanism of increased glucose-stimulated insulin secretion (GSIS) during persistent ER stress in pancreatic ? cells via the upregulation of the nutrient-sensing mitochondrial GTP dependent pathway.

Public Health Relevance

We will study the novel concept that understanding the mechanism of adaptation to chronic endoplasmic reticulum stress before development of disease may lead to therapeutics to delay/prevent disease onset. There is a clear link between diabetes and induction of ER stress in insulin producing ? cells. We will identify the adaptive to ER stress mechanisms in ? cells. These studies will lead to the discovery of biomarkers in progression of diabetes, as well as development of drugs to enhance adaptation and ? cell survival. In addition, the findings should facilitate the design of drugs to fine-tune insulin synthesis in Type 1 and Type 2 diabetes to functional levels that minimize ER stress in ? cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053307-22
Application #
9725963
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Wang, Xujing
Project Start
1998-01-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
22
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Dery?o, Kamil; Michalec-WawiĆ³rka, Barbara; Krokowski, Dawid et al. (2018) The uL10 protein, a component of the ribosomal P-stalk, is released from the ribosome in nucleolar stress. Biochim Biophys Acta Mol Cell Res 1865:34-47
Yadav, Vinita; Gao, Xing-Huang; Willard, Belinda et al. (2017) Hydrogen sulfide modulates eukaryotic translation initiation factor 2? (eIF2?) phosphorylation status in the integrated stress-response pathway. J Biol Chem 292:13143-13153
Roy, Debasish; Farabaugh, Kenneth T; Wu, Jing et al. (2017) Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator-activated receptor ? (PPAR?) during adipocyte differentiation. J Biol Chem 292:14827-14835
Krokowski, Dawid; Guan, Bo-Jhih; Wu, Jing et al. (2017) GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells. Cell Rep 21:2895-2910
Ziosi, Marcello; Di Meo, Ivano; Kleiner, Giulio et al. (2017) Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Mol Med 9:96-111
Guan, Bo-Jhih; van Hoef, Vincent; Jobava, Raul et al. (2017) A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell 68:885-900.e6
Farabaugh, Kenneth T; Majumder, Mithu; Guan, Bo-Jhih et al. (2017) Protein Kinase R Mediates the Inflammatory Response Induced by Hyperosmotic Stress. Mol Cell Biol 37:
Hsu, K-S; Guan, B-J; Cheng, X et al. (2016) Translational control of PML contributes to TNF?-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs. Cell Death Differ 23:469-83
Golovko, Andrei; Kojukhov, Artyom; Guan, Bo-Jhih et al. (2016) The eIF2A knockout mouse. Cell Cycle 15:3115-3120
Abbas, Ahmed; Beamish, Christine; McGirr, Rebecca et al. (2016) Characterization of 5-(2- 18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas. F1000Res 5:1851

Showing the most recent 10 out of 62 publications