The cellular response to nutritional and environmental stress has been associated with the pathology of many diseases. Major contributors to cell fate decisions in response to stress are: (i) cell-type specific factors, (ii) time and (iii) intensity of stress. Chronic and high intensity stress conditions attenuate survival and favor apoptosis. The best-studied physiological stress conditions that are related to human disease are endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded proteins in the ER (diabetes, obesity, cancer) and oxidative stress, which results in increased reactive oxygen species (R08) and disruption of physiological R08 Signaling (neurodegeneration). Hypeosmotic stress is less-well studied. However, the major pathology with hyperosmotic stress is induction of the inflammatory response via increased expression of NF-kB target genes. The mechanisms that control inflammation and cellular recovery from hypeosmotic stress and specifically regulation of mRNA translation are not known. Because cells activate survival and apoptotic signals in response to stress, the interplay between these competing signals is crucial for elucidating adaptation and death mechanisms. We propose to study: 1. The functions of recently discovered cytoplasmic RNA-protein complexes in the response to hyperosmotic stress 2. Test the hypothesis that oxidation of cysteines drives HnRNPA 1 out of the nucleus during hyperosmotic stress and this cytoplasmic accumulation promotes apoptosis via translational control mechanisms. 3. The mechanisms of translational control during hyperosmotic stress. We propose a novel mechanism that controls ribosomal subunit availability and function that involves induction of autophagy 4. The mechanism via which the signaling of elF2? phosphorylation inhibits adaptation and promotes inflammatory mechanisms in response to hyperosmotic cells.

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 #
5R37DK060596-18
Application #
9671871
Study Section
Special Emphasis Panel (NSS)
Program Officer
Maruvada, Padma
Project Start
2016-06-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
18
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
Krishnamoorthy, Jothilatha; Tenkerian, Clara; Gupta, Jyotsana et al. (2018) Downregulation of PERK activity and eIF2? serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells. Cell Death Dis 9:254
Dasarathy, Srinivasan; Hatzoglou, Maria (2018) Hyperammonemia and proteostasis in cirrhosis. Curr Opin Clin Nutr Metab Care 21:30-36
Ko, Chih-Wei; Counihan, Daniel; Wu, Jing et al. (2018) Macrophages with a deletion of the phosphoenolpyruvate carboxykinase 1 (Pck1) gene have a more proinflammatory phenotype. J Biol Chem 293:3399-3409
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
Choi, Woo-Gyun; Han, Jaeseok; Kim, Ji-Hyeon et al. (2017) eIF2? phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet. Nutr Metab (Lond) 14:48
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

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