Translational control by nutrients

营养物质的翻译控制

基本信息

批准号：
10662521
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
项目类别：
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/10662521
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 Cellular biology Code Cytoplasmic Granules Data Defect Dehydration Diabetes Mellitus Disease Dry Eye Syndromes Epithelial Cells Exposure to Eye FRAP1 gene Future G3BP1 gene Genetic Transcription 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 Translational Regulation Translations Water balance testing biological adaptation to stress cell type corneal epithelium environmental change experience exposed human population insight link protein mRNA Translation molecular marker novel predictive modeling programs response ribosome profiling therapeutic development transcriptome transcriptome sequencing transcriptomics

项目摘要

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功能至关重要。经常挑战是脱水，它增加了导致水损失和细胞收缩的细胞上的渗透压。细胞通过累积有机渗透剂来响应以适应细胞体积和离子强度的降低在称为osmoadaptation的过程中。这种细胞应激反应对于所有生物的生存至关重要，组织。渗透压的缺陷引起了降低细胞存活的促炎计划，并具有对多种病理的影响，包括炎症性肠病，糖尿病，癌症和干眼症综合征。与糖尿病相关的高血糖高质量综合征（HHS）正在危及生命。因此是重要的是了解渗透压的分子机制。我们的申请专注于调节渗透压过程中蛋白质合成的调节，这是一个关键的过程，被理解不足。总体该提案的目标是对翻译法规的机械性，全转录组的理解在渗透压期间，将导致疾病疗法的发展，导致组织减少渗透压。我们将检查关键调节器的功能，包括用于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发展糖尿病干眼症综合征病理学的细胞。发展对渗透压期间翻译调节的机械，转录组的理解表征渗透压期间翻译景观并定义调节性RNA特征控制mRNA翻译的变化（AIM 1）。然后，我们专注于翻译之间的相互作用 RNA结合蛋白（RBPS）的调节，氨基酸稳态和液态液相分离（LLP）在osmoadaptation期间，并描绘了mTOR和SNAT2活动如何影响翻译景观对高渗性压力的反应（AIM 2）。最后，我们检查了RBP的功能，该功能将LLP和翻译调节，通过确定特定RBP的RNA结合模式和LLP在 osmoadaptation（AIM 3）。

项目成果

期刊论文数量（52）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A stress-responsive RNA switch regulates VEGFA expression.

DOI：
10.1038/nature07598
发表时间：
2009-02-12
期刊：
NATURE
影响因子：
64.8
作者：
Ray, Partho Sarothi;Jia, Jie;Yao, Peng;Majumder, Mithu;Hatzoglou, Maria;Fox, Paul L.
通讯作者：
Fox, Paul L.

A tale of two proteins: PACT and PKR and their roles in inflammation.

DOI：
10.1111/febs.15691
发表时间：
2021-11
期刊：
The FEBS journal
影响因子：
0
作者：
通讯作者：

Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle.

尽管肝脏和骨骼肌减少，但响应急性禁食和长期食物限制，心脏中的蛋白质合成得以保留。

DOI：
10.1152/ajpendo.00545.2007
发表时间：
2008
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Yuan,CelvieL;Sharma,Naveen;Gilge,DanielleA;Stanley,WilliamC;Li,Yi;Hatzoglou,Maria;Previs,StephenF
通讯作者：
Previs,StephenF

An efficient in vitro translation system from mammalian cells lacking the translational inhibition caused by eIF2 phosphorylation.

来自哺乳动物细胞的有效体外翻译系统，缺乏 eIF2 磷酸化引起的翻译抑制。

DOI：
10.1261/rna.825008
发表时间：
2008
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Zeenko,VladimirV;Wang,Chuanping;Majumder,Mithu;Komar,AntonA;Snider,MartinD;Merrick,WilliamC;Kaufman,RandalJ;Hatzoglou,Maria
通讯作者：
Hatzoglou,Maria

Autophagy impairment as a key feature for acetaminophen-induced ototoxicity.

自噬损伤是对乙酰氨基酚诱导的耳毒性的一个关键特征

DOI：
10.1038/s41419-020-03328-6
发表时间：
2021-01-04
期刊：
Cell death & disease
影响因子：
9
作者：
Zhao T;Zheng T;Yu H;Hu BH;Hu B;Ma P;Yang Y;Yang N;Hu J;Cao T;Chen G;Yan B;Peshoff M;Hatzoglou M;Geng R;Li B;Zheng QY
通讯作者：
Zheng QY