Temporal coordination of stimulus-induced gene expression by RNA-binding proteins

RNA结合蛋白刺激诱导的基因表达的时间协调

基本信息

批准号：
10671719
负责人：
Neelanjan Mukherjee
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671719
关键词：
Adrenal Glands Aldosterone Angiotensin II Attenuated Binding Binding Proteins Biological Models Blood Pressure Cells Cholesterol Ensure Gene Expression Gene Expression Regulation Genetic Transcription Goals Human Kinetics Ligands Messenger RNA Methods Pattern Peptides Phenotype Physiologic pulse Play Post-Transcriptional Regulation Prevention Production RNA RNA Decay RNA Processing RNA-Binding Proteins Research Resolution Role Steroid biosynthesis Stimulus System Testing Textbooks Translations ZFP36L2 gene Zona Glomerulosa cytokine immune activation innovation insight mRNA Decay mRNA Expression mRNA Translation posttranscriptional programs receptor response

Adrenal Glands Aldosterone Angiotensin II Attenuated Binding Binding Proteins Biological Models Blood Pressure Cells Cholesterol Ensure Gene Expression Gene Expression Regulation Genetic Transcription Goals Human Kinetics Ligands Messenger RNA Methods Pattern Peptides Phenotype Physiologic pulse Play Post-Transcriptional Regulation Prevention Production RNA RNA Decay RNA Processing RNA-Binding Proteins Research Resolution Role Steroid biosynthesis Stimulus System Testing Textbooks Translations ZFP36L2 gene Zona Glomerulosa cytokine immune activation innovation insight mRNA Decay mRNA Expression mRNA Translation posttranscriptional programs receptor response

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项目摘要

SUMMARY Cellular responses to external stimuli require dynamic gene regulation to facilitate rapid activation and effective resolution. Although transcriptional responses are a textbook mechanism for stimulus-induced responses, post- transcriptional regulation of mRNA translation and decay are the other side of the coin and are essential for rapid and adaptable stimulus-induced responses. For example, immune activation generates a prototypical temporal expression pattern for cytokine mRNAs known as an impulse response, which is a rapid pulse-like increase and decrease in expression. The destabilization of cytokine mRNAs is required for proper resolution of the impulse response and prevention of excess cytokine production. It is increasingly recognized that RNA-binding proteins (RBPs) play critical roles in achieving an appropriate stimulus-induced gene expression response by regulating RNA processing, decay, and translation of target RNAs. The over-arching goal of our research program is to understand how RBPs temporally coordinate stimulus-induced gene expression and cellular phenotypes. The model system we will use to study how dynamic RBP-RNA regulatory interactions temporally coordinate stimulus-induced gene expression is human adrenal steroidogenesis. This is a classic ligand-induced system in which the small peptide Angiotensin II (AngII) binds to its receptor in adrenal zona glomerulosa cells to stimulate the production of aldosterone, the master regulator of blood pressure. Thus, tight control of regulatory timing is required since it must be rapidly produced de novo from cholesterol in response to AngII. We have recently demonstrated that AngII treatment of immortalized and primary adrenocortical cells results in an impulse response. Furthermore, we found specific RBPs and regulated RNA decay facilitates the rapid implementation and resolution of the AngII impulse response. In this proposal, we will test the hypothesis that MSI2 and ZFP36L2 are counteracting forces that, respectively, potentiate and attenuate the kinetics of stimulus-induced mRNA levels by modulating target mRNA decay and translation, to ensure the proper timing and amplitude of the impulse response. We will utilize cutting edge methods to gain temporal and quantitative insights into how stimulus-induced changes in RBP binding determine changes in target mRNA expression responses and ultimately cellular phenotype. The use of innovative approaches we use will help shift the field from a static to a dynamic view of RBP-mRNA interactions and achieve mechanistic insight on how regulatory RBP-mRNA interactions control mRNA fate decisions to govern cellular responses.