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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Maruvada, Padma
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Case Western Reserve University
Schools of Medicine
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