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: 7393796
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393796
• 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

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，成人心脏肥厚是由多种因素引起的