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 signals and favor apoptotic signals. This proposal will explore the molecular mechanisms of cell fate decisions during hypertonic stress. Hypertonic stress causes loss of intracellular water, cell shrinkage and macromolecular crowding. Disease-related examples are hyperglycemia in diabetes (HHS, Hyperglycemic Hyperosmolar State), macrophage cell death in inflammatory sites, dehydration of the ocular surface in dry eye syndrome and increased susceptibility to infections and retinal cell apoptosis in diabetic retinopathy. During the previous grant cycle we were the first to identify a novel pathway that promotes cell death during hypertonic stress. We showed that a specific signaling pathway (eIF21-P), the master regulator of survival and apoptotic signals in all stress responses, mediates the cytoplasmic localization of a nuclear protein that represses synthesis of proteins that promote cell survival. This cellular response shifts the balance to cell death (apoptosis) by weakening the survival mechanisms of the stressed cells. Regulation of the subcellular localization of nuclear proteins by extracellular signaling is an understudied and emerging area of research. We propose to identify some of the critical factors which are involved in the switch of balance from survival to apoptosis during hypertonic stress. We will determine (i) the signaling pathways that affect translation of mRNAs coding for proteins that determine cell fate during hypertonic stress. (ii) specific signaling molecules (cleaved tRNAs) involved in inhibition of protein synthesis during hypertonic stress and (iii) the effect of inflammation in hypertonic stress-induced cell death in a model of human disease. These studies will increase our understanding of stress-induced human diseases and generate biological markers that can be used for drug development.
A recently recognized pathology is the increased extracellular osmolarity at sites of inflammation. Increased extracellular osmolarity causes osmotic stress, which leads to loss of intracellular water, cell shrinkage, macromolecular crowding and death. Diseases such as diabetic retinopathy, Hyperglycemic Hyperosmolar State (HHS) in diabetes, macrophage cell death at inflammatory sites, and dehydration of the ocular surface in dry eye syndrome are some examples that involve increased systemic or local extracellular osmolarity. The studies in this proposal will bring new insights into the molecular events that determine cell fate when osmolarities increase above normal and will assist in the development of drugs to attenuate undesirable apoptosis of healthy cells.
|Davuluri, Gangarao; Krokowski, Dawid; Guan, Bo-Jhih et al. (2016) Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis. J Hepatol 65:929-937|
|Hao, Yujun; Samuels, Yardena; Li, Qingling et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971|
|Kenche, Harshavardhan; Ye, Zhi-Wei; Vedagiri, Kokilavani et al. (2016) Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase. J Biol Chem 291:4763-78|
|Hsu, K-S; Guan, B-J; Cheng, X et al. (2016) Translational control of PML contributes to TNFÎ±-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs. Cell Death Differ 23:469-83|
|Saikia, Mridusmita; Hatzoglou, Maria (2015) The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health. J Biol Chem 290:29761-8|
|Komar, Anton A; Hatzoglou, Maria (2015) Exploring Internal Ribosome Entry Sites as Therapeutic Targets. Front Oncol 5:233|
|Majumder, Mithu; Mitchell, Daniel; Merkulov, Sergei et al. (2015) Residues required for phosphorylation of translation initiation factor eIF2Î± under diverse stress conditions are divergent between yeast and human. Int J Biochem Cell Biol 59:135-41|
|Schuster, Andrew T; Homer, Craig R; Kemp, Jacqueline R et al. (2015) Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. Gastroenterology 148:1405-16.e3|
|Gao, Xing-Huang; Krokowski, Dawid; Guan, Bo-Jhih et al. (2015) Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response. Elife 4:e10067|
|Merry, Callie R; Forrest, Megan E; Sabers, Jessica N et al. (2015) DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet 24:6240-53|
Showing the most recent 10 out of 26 publications