Translational control by nutrients

营养物质的翻译控制

• 批准号: 10528755
• 负责人: MARIA HATZOGLOU
• 金额: $ 67.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528755
• 关键词: Address; Affect; Amino Acid Transporter; Amino Acids; Binding; Binding Proteins; Biological Process; Cell Death; Cell Survival; Cell Volumes; Cells; Cellular Assay; Cellular Stress Response; Cellular biology; Code; Cytoplasmic Granules; Data; Defect; Dehydration; Diabetes Mellitus; Disease; Dry Eye Syndromes; Epithelial Cells; Experimental Models; Exposure to; Eye; FRAP1 gene; Future; G3BP1 gene; Genetic Transcription; Genetic Translation; Goals; Homeostasis; Human; Hyperglycemia; Individual; Inflammatory; Inflammatory Bowel Diseases; Ionic Strengths; Knowledge; Life; Link; Liquid substance; Malignant Neoplasms; Measurement; Measures; Messenger RNA; Modeling; Molecular; Molecular Biology Techniques; Molecular Target; Nutrient; Organism; Osmolar Concentration; Osmotic Pressure; Pathologic; Pathology; Pattern; Phase; Physiological; Process; Protein Biosynthesis; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Reporter; Research; Stress; Syndrome; System; Therapeutic; Tissues; Transcript; Translations; Ursidae Family; Water; balance testing; biological adaptation to stress; cell type; cell water; corneal epithelium; environmental change; experience; exposed human population; insight; link protein; novel; predictive modeling; programs; response; ribosome profiling; targeted biomarker; therapeutic development; transcriptome; transcriptome sequencing; transcriptomics

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).

适应环境挑战的能力对于细胞和有机体功能至关重要。经常出现的 挑战是脱水，它会增加细胞的渗透压，导致水分流失和细胞收缩。 细胞通过积累有机渗透剂来适应细胞体积和离子强度的减少 在一个称为渗透适应的过程中。这种细胞应激反应对于所有生物体的生存至关重要 组织。渗透适应缺陷会诱发促炎程序，从而降低细胞存活率并导致细胞死亡。 对多种病理学的影响，包括炎症性肠病、糖尿病、癌症和干眼症 综合症。糖尿病相关的高血糖高渗综合征（HHS）危及生命。因此是 了解渗透适应的分子机制很重要。我们的应用重点是 渗透适应过程中蛋白质合成的调节，这是一个人们知之甚少的关键过程。整体 该提案的目标是对翻译调控建立机械的、转录组范围的理解 在渗透适应过程中，这将导致导致组织减少的疾病的治疗方法的发展 渗透压耐受性。我们将检查关键调节因子的功能，包括氨基转运蛋白 SNAT2 使用人角膜上皮细胞 (HCE) 建立渗透适应性 mRNA 翻译程序。角膜 上皮细胞是眼睛中形成糖尿病干眼综合征病理的细胞。发展 我们对渗透适应过程中翻译调节的机械性、转录组范围的理解 描述渗透适应过程中的翻译景观并定义调节性 RNA 特征 控制 mRNA 翻译的变化（目标 1）。然后我们关注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) 在渗透适应过程中，并描述 mTOR 和 SNAT2 活动如何影响翻译景观 对高渗应激的反应（目标 2）。最后，我们检查连接 LLPS 和 RBP 的功能 翻译调节，通过确定特定 RBP 的 RNA 结合模式和 LLPS 渗透适应（目标 3）。