Translational control by nutrients

适应环境挑战的能力对于细胞和生物体功能至关重要。经常 挑战是脱水，这增加了细胞上的渗透压，导致水分损失和细胞收缩。 细胞通过积累有机渗透物来适应细胞体积和离子强度的降低 这一过程被称为适应性调整。这种细胞应激反应对所有生物体的生存至关重要， 组织中细胞适应性缺陷诱导了一个促炎程序，减少了细胞存活， 对多种病理的影响，包括炎症性肠病、糖尿病、癌症和干眼 综合征糖尿病相关的高血糖高渗综合征（HHS）是一种危及生命的疾病。因此 重要的是要了解的分子机制的适应性。我们的应用程序侧重于 调节蛋白质的合成过程中的适应性，一个关键的过程，这是知之甚少。整体 这个建议的目标是发展一个机械的，转录组范围内的翻译调控的理解 这将导致发展治疗疾病的方法， 宽容。我们将研究关键调节因子的功能，包括氨基转运蛋白SNAT 2， 使用人角膜上皮细胞（HCE）建立角膜适应性mRNA翻译程序。角膜 上皮细胞是眼睛中的细胞，其发展糖尿病中的干眼综合征的病理。发展 一个机械的，转录组范围内的理解翻译调节过程中的转录适应，我们 描述了在转录适应过程中的翻译景观，并定义了调控RNA的特征， 控制mRNA翻译的变化（目的1）。然后我们重点讨论翻译之间的相互作用 RNA结合蛋白（RBP）的调节、氨基酸稳态和液-液相分离（LLPS） 并描述mTOR和SNAT 2活动如何影响翻译景观， 高渗应激反应（Aim 2）。最后，我们研究了连接LLPS和 翻译调控，通过确定RNA结合模式和特定RBP的LLPS， 适应性调整（目标3）。

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).