Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy

心脏肥大通常发生在新生儿心脏中，并且在成人心脏中，由各种 生理和病理状况，如局部缺血、高血压和甲状腺毒症。期间 在这个过程中，心肌细胞的大小增加，但数量不增加。我们的核心假设是， 确定心肌细胞核糖体RNA合成的调控机制， 靶点的干预和阐明信号转导途径，导致肥大。的 心肌细胞肥大的标志是总蛋白的积累。核糖体积累1）是 无论刺激如何，在肥大期间总是发生的一个关键适应性变化，2）是 加速蛋白质合成速率的主要机制，以及3）由增加的速率导致 核糖体RNA基因（rDNA）的转录。我们已经研究了rDNA的调控 在新生儿和成人心肌细胞肥大的几种模型中的转录。我们发现在 在包括主动脉缩窄在内的几种模型中，rDNA转录因子UBF的量增加 在心肌细胞中。UBF质量的增加与rDNA转录速率的增加平行， 这是由于UBF基因的表达增加。这个项目的一个目标是检验这个假设 UBF蛋白的增加是肥大生长所必需的。我们的研究结果表明，至少 一个调节心肌细胞rDNA转录的信号转导途径靶向UBF 基因我们的目标是通过定位UBF基因的顺式作用元件来确定该通路 在肾上腺素能药物或压力作用下， 超载。这些实验的结果将增加我们对信号转导的理解 导致心脏肥大过程的途径。

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.