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: 7102194
• 负责人: LAWRENCE I ROTHBLUM
• 金额: $ 36.19万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102194
• 关键词: RNA biosynthesis; cardiac myocytes; cell growth regulation; cell morphology; genetic enhancer element; genetic transcription; hypertension; laboratory rat; myocardial ischemia /hypoxia; ribosomal RNA; tissue /cell culture; transcription factor; ventricular hypertrophy

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，而在成人心脏中，心脏肥大是由各种生理和病理条件（例如缺血、高血压和甲状腺毒症）引起的。在此过程中，心肌细胞体积增大，但数量不变。我们的中心假设是，确定心肌细胞核糖体 RNA 合成的调节机制将为干预提供目标，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) 是一种关键的适应性变化，无论刺激如何，在肥大期间总是发生，2) 是加速蛋白质合成速率的主要机制，3) 是核糖体 RNA 基因转录速率增加的结果（ rDNA）。我们研究了几种新生儿和成人心肌细胞肥大模型中 rDNA 转录的调控。我们发现，在包括主动脉缩窄在内的多种模型中，心肌细胞中 rDNA 转录因子 UBF 的数量增加。 UBF 质量的增加与 rDNA 转录速率的增加相平行，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以下假设：UBF 蛋白的增加对于肥大性生长是必要的。我们的结果表明，至少一种调节心肌细胞中 rDNA 转录的信号转导途径以 UBF 基因为目标。我们的目标是通过绘制 UBF 基因的顺式作用元件来定义该途径，该元件负责响应肾上腺素能药物或压力超负荷而增加基因的表达。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途径的理解。