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

基本信息

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
项目类别：
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

项目摘要

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.

心脏肥大通常发生在新生儿心脏中，在成人心脏中，由各种心脏诱导生理和病理状况，例如缺血，高血压和甲状腺毒性。期间此过程的心脏肌肉细胞的大小增加，但数量不高。我们的中心假设是确定调节心肌细胞中核糖体RNA合成的机制将提供干预的目标并照亮导致肥大的信号转导途径。这心肌细胞肥大的标志是总蛋白的积累。核糖体积累1）是无论刺激如何加速蛋白质合成速率的主要机制，3）速率提高导致核糖体RNA基因（rDNA）的转录。我们检查了rDNA的调节在新生儿和成人心肌细胞肥大的几种模型中转录。我们发现在几种模型，包括主动脉缩窄，rDNA转录因子UBF的量增加在心肌细胞中。 UBF质量的增加与rDNA转录率的增加和由UBF基因的表达增加产生。该项目的目标之一是检验假设 UBF蛋白的增加是肥厚性生长所必需的。我们的结果表明至少一种调节心肌细胞RDNA转录的信号转导途径靶向UBF 基因。我们的目标是通过映射UBF基因的顺式作用元素来定义途径负责响应肾上腺素能或压力的基因表达增加超载。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。