Translational Control by Osmotically Active Solutes

描述(申请人提供)：细胞对营养和环境压力的反应与许多疾病的病理有关。决定细胞命运的主要因素是：(I)细胞类型的特定因素，(Ii)时间和(Iii)压力强度。慢性和高强度的应激状态会减弱生存信号，有利于凋亡信号。这一建议将探索在高渗应激过程中决定细胞命运的分子机制。高渗应激导致细胞内水分丢失、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，高血糖高渗透状态)，炎症部位的巨噬细胞死亡，干眼综合征的眼表脱水，以及糖尿病视网膜病变的感染易感性和视网膜细胞凋亡。在之前的资助周期中，我们第一个发现了一种在高渗应激过程中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)，它是所有应激反应中生存和凋亡信号的主要调节因子，介导了核蛋白的细胞质定位，抑制了促进细胞存活的蛋白质的合成。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)上。通过细胞外信号调节核蛋白的亚细胞定位是一个研究不足的新兴研究领域。我们建议确定一些关键因素，这些因素参与了在高渗应激过程中从生存到凋亡的平衡转换。我们将确定(I)在高渗应激过程中影响编码决定细胞命运的蛋白质的mRNAs翻译的信号通路。(Ii)参与高渗应激期间蛋白质合成抑制的特定信号分子(裂解tRNAs)和(Iii)炎症在高渗应激诱导的人类疾病模型细胞死亡中的作用。这些研究将增加我们对压力引起的人类疾病的理解，并产生可用于药物开发的生物标记。

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.