Translational Control by Osmotically Active Solutes

描述（由申请人提供）：细胞对营养和环境应激的反应与许多疾病的病理有关。影响细胞在应激反应中命运决定的主要因素有：(i)细胞类型特定因素，（ii）时间和（iii）应激强度。慢性和高强度应激条件减弱生存信号和有利于凋亡信号。本研究将探讨高渗应激下细胞命运决定的分子机制。高渗应激导致细胞内水分流失、细胞收缩和大分子拥挤。与疾病相关的例子有糖尿病的高血糖（HHS，高血糖高渗状态），炎症部位的巨噬细胞死亡，干眼综合征的眼表脱水，糖尿病视网膜病变的感染易感性增加和视网膜细胞凋亡。在之前的资助周期中，我们首次发现了一种在高渗应激下促进细胞死亡的新途径。我们发现了一个特定的信号通路（eIF21-P），在所有应激反应中生存和凋亡信号的主要调节器，介导核蛋白的细胞质定位，抑制促进细胞生存的蛋白质的合成。这种细胞反应通过削弱应激细胞的生存机制，将平衡转移到细胞死亡（凋亡）。通过细胞外信号调控核蛋白的亚细胞定位是一个未被充分研究的新兴研究领域。我们建议确定一些在高渗应激下从存活到凋亡的平衡转换中涉及的关键因素。我们将确定(i)影响高渗应激下决定细胞命运的蛋白质编码mrna翻译的信号通路。（ii）在高渗应激期间参与抑制蛋白质合成的特定信号分子（裂解trna）和（iii）在人类疾病模型中，炎症在高渗应激诱导的细胞死亡中的作用。这些研究将增加我们对压力诱导的人类疾病的理解，并产生可用于药物开发的生物标记物。

DESCRIPTION (provided by applicant): 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.