Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy

核糖体生物发生：心脏肥大的分子检查点

• 批准号: 7597228
• 负责人: LAWRENCE I ROTHBLUM
• 金额: $ 35.56万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7597228
• 关键词: Adrenergic Agents; Adult; Affect; Animal Model; Aortic coarctation; Biogenesis; Cardiac; Cardiac Myocytes; Data; Dominant-Negative Mutation; Down-Regulation; Endothelin-1; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Heart; Heart Hypertrophy; Hypertension; Hypertrophy; Intervention; Ischemia; Lead; Left Ventricular Hypertrophy; Maps; Messenger RNA; Modeling; Molecular; Neonatal; Pathway interactions; Phosphorylation; Physiological; Process; Protein Biosynthesis; Proteins; RNA chemical synthesis; Rattus; Recombinant DNA; Regulation; Ribosomal RNA; Ribosomes; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Stimulus; Structure; Testing; Thyrotoxicosis; Trans-Activators; adrenergic; base; cis acting element; in vivo; overexpression; pressure; prevent; rRNA Genes; research study; response; tissue culture; transcription factor; transcription factor UBF

Cardiac hypertrophy occurs normally in neonatal hearts and, in adult hearts, is induced by various physiological and pathological conditions such as ischemia, hypertension, and thyrotoxicosis. During this process the cardiac muscle cells increase in size but not in number. Our central hypothesis is that the determination of the mechanisms regulating ribosomal RNA synthesis in cardiomyocytes will provide targets for intervention and illuminate the signal transduction pathways that lead to hypertrophy. The hallmark of cardiomyocyte hypertrophy is the accumulation of total protein. Ribosome accumulation 1) is a key adaptive change that always occurs during hypertrophy, regardless of the stimulus, 2) is the primary mechanism for accelerating the rate of protein synthesis, and 3) results from an increased rate of transcription of the ribosomal RNA genes (rDNA). We have examined the regulation of rDNA transcription in several models of neonatal and adult cardiomyocyte hypertrophy. We found that in several models, including aortic coarctation, the amount of the rDNA transcription factor UBF increased in the cardiomyocytes. The increase in UBF mass parallels the increased rate of rDNA transcription and resulted from increased expression of the UBF gene. One goal of this project is to test the hypothesis that the increase in UBF protein is necessary for hypertrophic growth. Our results suggest that at least one signal transduction pathway that regulates rDNA transcription in cardiomyocytes targets the UBF gene. Our goal is to define the pathway by mapping the cis-acting elements of the UBF gene responsible for increased expression of the gene in response to either adrenergic agents or pressure overload. The results of these experiments will increase our understanding of the signal transduction pathway(s) that lead to the process of cardiac hypertrophy.

心肌肥厚通常发生在新生儿心脏，而在成人心脏，则由多种因素引起 生理和病理状态，如缺血、高血压和甲亢。在.期间 在这个过程中，心肌细胞大小增加，但数量没有增加。我们的中心假设是 心肌细胞核糖体RNA合成调控机制的确定将提供 干预的靶点，阐明导致肥大的信号转导通路。这个 心肌细胞肥大的标志是总蛋白的积累。核糖体积累1)是 在肥厚期间总是发生的一个关键的适应性变化，无论是什么刺激，2)是 加速蛋白质合成速度的主要机制，以及3)提高合成速度的结果 核糖体RNA基因(RDNA)的转录。我们研究了rdna的调控。 几种新生儿和成人心肌细胞肥大模型中的转录。我们发现这一点 包括主动脉缩窄在内的几种模型中，rDNA转录因子ubf的数量增加。 在心肌细胞中。UBF质量的增加与rDNA转录和 这是由于UBF基因表达增加所致。这个项目的一个目标是检验这一假设 UBF蛋白的增加是肥大生长所必需的。我们的结果表明，至少 调节心肌细胞rDNA转录的一条信号转导通路以UBF为靶点 吉恩。我们的目标是通过定位UBF基因的顺式作用元件来确定该途径 负责对肾上腺素能药物或压力做出反应的基因表达增加 超载。这些实验的结果将加深我们对信号转导的理解 导致心肌肥大过程的通路(S)。

项目成果

UBF levels determine the number of active ribosomal RNA genes in mammals.

• DOI: 10.1083/jcb.200805146
• 发表时间: 2008-12-29
• 期刊: The Journal of cell biology
• 作者: Sanij E;Poortinga G;Sharkey K;Hung S;Holloway TP;Quin J;Robb E;Wong LH;Thomas WG;Stefanovsky V;Moss T;Rothblum L;Hannan KM;McArthur GA;Pearson RB;Hannan RD
• 通讯作者: Hannan RD