Document text
Principal Investigator: MARIA HATZOGLOU
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $650,207
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
The ability to adapt to environmental challenges is critical for cellular and organismal function. A frequent
challenge is dehydration which increases osmotic pressure on the cells causing water loss and cell shrinkage.
Cells respond by accumulating organic osmolytes to accommodate decreases in cell volume and ionic strength
in a process called osmoadaptation. This cellular stress response is critical for survival of all organisms and
tissues. Defects in osmoadaptation induce a pro-inflammatory program that decreases cell survival and has
implications for multiple pathologies, including inflammatory bowel disease, diabetes, cancer and dry eye
syndrome. Diabetes associated hyperglycemic hyperosmolar syndrome (HHS) is life threatening. It is therefore
important to understand the molecular mechanisms of osmoadaptation. Our application focuses on the
regulation of protein synthesis during osmoadaptation, a critical process that is poorly understood. The overall
goal of this proposal is to develop a mechanistic, transcriptome-wide understanding of translation regulation
during osmoadaptation that will lead to development of therapeutics of diseases that cause decreased tissue
osmotolerance. We will examine the function of key regulators, including the amino transporter SNAT2 for
establishing osmoadaptive mRNA translation programs using Human Corneal Epithelial Cells (HCEs). Corneal
Epithelial cells are the cells in the eye that develop the pathology of dry eye syndrome in diabetes. To develop
a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation we
characterize the translation landscape during osmoadaptation and define the regulatory RNA features that
control the changes in mRNA translation (Aim 1). We then focus on the interplay between translation
regulation, amino acid homeostasis and liquid-liquid phase separation (LLPS) of RNA binding proteins (RBPs)
during osmoadaptation and delineate how mTOR and SNAT2 activities affect the translation landscape in
response to hyperosmotic stress (Aim 2). Finally, we examine the function of RBPs that link LLPS and
translation regulation, by determining RNA binding patterns and LLPS for specific RBPs during
osmoadaptation (Aim 3).
Terms: <Address><Affect><Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Amino Acids><Autoregulation><Binding><Binding Proteins><Biological Function><Biological Process><Body Tissues><Cancers><Cell Body><Cell Death><Cell Survival><Cell Viability><Cell Volumes><Cells><Cellular Assay><Cellular Stress><Cellular Stress Response><Cellular biology><Code><Coding System><Cytoplasmic Granules><Data><Defect><Dehydration><Diabetes Mellitus><Disease><Disorder><Dry Eye Syndromes><Dry eye disease><Epithelial Cells><Exposure to><Eye><Eyeball><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Future><G3BP><G3BP1><G3BP1 gene><Gene Transcription><Genetic Transcription><Goals><Homeostasis><Human><Hydrogen Oxide><Hyperglycemia><Individual><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Ionic Strengths><Keratoconjunctivitis Sicca><Knowledge><Life><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Liquid substance><Malignant Neoplasms><Malignant Tumor><Measurement><Measures><Mechanistic Target of Rapamycin><Messenger RNA><Modeling><Modern Man><Molecular><Molecular Biology Techniques><Molecular Interaction><Molecular Target><Non-Polyadenylated RNA><Nutrient><Organism><Osmolar Concentration><Osmolarity><Osmotic Pressure><Pathologic><Pathology><Pattern><Phase><Physiologic><Physiological><Physiological Homeostasis><Process><Protein Binding><Protein Biosynthesis><RAFT1><RNA><RNA Binding><RNA Expression><RNA Gene Products><RNA Seq><RNA bound><RNA sequencing><RNA-Binding Proteins><RNAseq><Regulation><Reporter><Research><Ribo-seq><Ribonucleic Acid><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Stress><Syndrome><System><Therapeutic><Tissues><Transcript><Transcription><Translational Regulation><Translations><Water><aminoacid><balance testing><biological adaptation to stress><body water dehydration><bound protein><cartilage link protein><cell assay><cell biology><cell stress><cell type><computer based prediction><corneal epithelial><corneal epithelium><diabetes><environmental change><experience><exposed human population><fluid><global gene expression><global transcription profile><granule><human exposure><hyperglycemic><inflammatory disease of the intestine><inflammatory disorder of the intestine><insight><intestinal autoinflammation><link protein><liquid><living system><mRNA><mRNA Translation><mTOR><malignancy><mammalian target of rapamycin><molecular biomarker><molecular marker><necrocytosis><neoplasm/cancer><novel><predictive modeling><programs><protein synthesis><reaction; crisis><response><ribosome footprint profiling><ribosome profiling><stress response><stress; reaction><therapeutic agent development><therapeutic development><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translation>