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: 7216335
• 负责人: LAWRENCE I ROTHBLUM
• 金额: $ 4.11万
• 依托单位: GEISINGER CLINIC
• 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 2007-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216335
• 关键词: Adrenergic Agents; Adult; Affect; Animal Model; Aortic coarctation; Biogenesis; Cardiac; Cardiac Myocytes; Condition; 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; Numbers; Pathway interactions; Phosphorylation; Physiological; Process; Protein Biosynthesis; Protein Overexpression; Proteins; RNA chemical synthesis; Rate; Rattus; Recombinant DNA; Regulation; Ribosomal DNA; Ribosomal RNA; Ribosomes; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Stimulus; Structure; Testing; Thyrotoxicosis; Trans-Activators; adrenergic; base; cis acting element; in vivo; pressure; prevent; rRNA Genes; research study; response; size; tissue culture; transcription factor; transcription factor UBF

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：心脏肥大通常发生在新生儿心脏中，在成人心脏中，由各种生理和病理条件如缺血、高血压和甲状腺毒症诱导。在这个过程中，心肌细胞的大小增加，但数量不增加。我们的中心假设是，确定心肌细胞中核糖体RNA合成的调节机制将为干预提供靶点，并阐明导致肥大的信号转导途径。心肌细胞肥大的标志是总蛋白的积累。核糖体积累1）是在肥大期间总是发生的关键适应性变化，无论刺激如何，2）是加速蛋白质合成速率的主要机制，3）是核糖体RNA基因（rDNA）转录速率增加的结果。我们研究了几种新生儿和成人心肌细胞肥大模型中rDNA转录的调节。我们发现在包括主动脉缩窄在内的几种模型中，心肌细胞中rDNA转录因子UBF的量增加。UBF质量的增加与rDNA转录速率的增加平行，并且是由UBF基因表达增加引起的。该项目的一个目标是检验UBF蛋白的增加是肥大生长所必需的假设。我们的研究结果表明，至少有一个信号转导途径，调节心肌细胞rDNA转录的目标UBF基因。我们的目标是通过绘制UBF基因的顺式作用元件来定义该通路，该元件负责肾上腺素能药物或压力过载时基因表达增加。这些实验的结果将增加我们对导致心脏肥大过程的信号转导通路的理解。