Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy

描述（由申请人提供）：心脏肥大通常发生在新生儿心脏，而在成人心脏中，是由各种生理和病理条件如缺血、高血压和甲状腺毒症引起的。在这个过程中，心肌细胞的大小增加，但数量没有增加。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)是一种关键的适应性变化，在肥大过程中总是发生，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转录的调控。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的数量增加。UBF质量的增加与rDNA转录率的增加是平行的，这是由于UBF基因表达的增加。该项目的目标之一是验证UBF蛋白的增加是肥厚生长所必需的假设。我们的研究结果表明，在心肌细胞中至少有一种调节rDNA转录的信号转导途径以UBF基因为靶点。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，该基因负责在肾上腺素能药物或压力过载的反应中增加基因的表达。这些实验的结果将增加我们对导致心脏肥厚过程的信号转导途径的理解。

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.