Translational Control by Osmotically Active Solutes

细胞对营养和环境压力的反应与 许多疾病的病理学。应激反应中细胞命运决定的主要因素是：(I) 细胞类型的具体因素，(Ii)时间和(Iii)应激强度。慢性高强度应激 条件会降低存活率，并有利于细胞凋亡。研究最深入的生理压力 与人类疾病相关的条件是内质网(ER)应激，这是 由内质网(糖尿病、肥胖、癌症)中未折叠蛋白的积累引起 氧化应激，导致活性氧物种增加(R08)和破坏 生理性R08信号(神经退行性变)。对高渗应激的研究较少。 然而，高渗应激的主要病理机制是诱导炎症反应。 通过增加核因子-kB靶基因的表达。控制炎症和炎症的机制 细胞从高渗应激中的恢复和对mRNA翻译的特异性调节不是 为人所知。因为细胞在应对压力时激活了生存和凋亡信号，所以这种相互作用 这些相互竞争的信号之间的关系对于阐明适应和死亡机制至关重要。我们 建议研究： 1.新近发现的细胞质RNA-蛋白质复合体在抗病反应中的作用 高渗应激 2.验证半胱氨酸的氧化将HnRNPA 1赶出细胞核的假设 高渗应激和这种细胞质堆积通过翻译促进细胞凋亡 控制机制。 3.高渗胁迫下的翻译调控机制。我们提议写一部小说 一种控制核糖体亚基可用性和功能的机制，涉及诱导 自噬 4.elF2α磷酸化信号转导抑制适应和 促进炎症机制对高渗细胞的反应。

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 elF2α phosphorylation inhibits adaptation and promotes inflammatory mechanisms in response to hyperosmotic cells.