Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
批准号:
7597228
负责人:
LAWRENCE I ROTHBLUM
金额:
$35.56万
依托单位国家:
美国
项目类别:
财政年份:
2006
资助国家:
美国
项目状态:
已结题
起止时间:
2006-04-01 至 2011-03-31
关键词:
Adrenergic AgentsAdultAffectAnimal ModelAortic coarctationBiogenesisCardiacCardiac MyocytesDataDominant-Negative MutationDown-RegulationEndothelin-1Gene ExpressionGenesGenetic TranscriptionGoalsGrowthHeartHeart HypertrophyHypertensionHypertrophyInterventionIschemiaLeadLeft Ventricular HypertrophyMapsMessenger RNAModelingMolecularNeonatalPathway interactionsPhosphorylationPhysiologicalProcessProtein BiosynthesisProteinsRNA chemical synthesisRattusRecombinant DNARegulationRibosomal RNARibosomesSignal PathwaySignal Transduction PathwaySmall Interfering RNAStimulusStructureTestingThyrotoxicosisTrans-Activatorsadrenergicbasecis acting elementin vivooverexpressionpressurepreventrRNA Genesresearch studyresponsetissue culturetranscription factortranscription factor UBF
中文摘要
心肌肥厚通常发生在新生儿心脏,而在成人心脏,则由多种因素引起
生理和病理状态,如缺血、高血压和甲亢。在.期间
在这个过程中,心肌细胞大小增加,但数量没有增加。我们的中心假设是
心肌细胞核糖体RNA合成调控机制的确定将提供
干预的靶点,阐明导致肥大的信号转导通路。这个
心肌细胞肥大的标志是总蛋白的积累。核糖体积累1)是
在肥厚期间总是发生的一个关键的适应性变化,无论是什么刺激,2)是
加速蛋白质合成速度的主要机制,以及3)提高合成速度的结果
核糖体RNA基因(RDNA)的转录。我们研究了rdna的调控。
几种新生儿和成人心肌细胞肥大模型中的转录。我们发现这一点
包括主动脉缩窄在内的几种模型中,rDNA转录因子ubf的数量增加。
在心肌细胞中。UBF质量的增加与rDNA转录和
这是由于UBF基因表达增加所致。这个项目的一个目标是检验这一假设
UBF蛋白的增加是肥大生长所必需的。我们的结果表明,至少
调节心肌细胞rDNA转录的一条信号转导通路以UBF为靶点
吉恩。我们的目标是通过定位UBF基因的顺式作用元件来确定该途径
负责对肾上腺素能药物或压力做出反应的基因表达增加
超载。这些实验的结果将加深我们对信号转导的理解
导致心肌肥大过程的通路(S)。
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1083/jcb.200805146
发表时间:
2008-12-29
期刊:
The Journal of cell biology
影响因子:
--
作者:
[Sanij E, Poortinga G, Sharkey K, Hung S, Holloway TP, Quin J, Robb E, Wong LH, Thomas WG, Stefanovsky V, Moss T, Rothblum L, Hannan KM, McArthur GA, Pearson RB, Hannan RD]
通讯作者:
Hannan RD
PHOSPHORYLATION OF RRN3
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批准号:7723048
-
项目类别:
-
资助金额:$0.32万
-
财政年份:2008
-
负责人:LAWRENCE I ROTHBLUM
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依托单位:
PHOSPHORYLATION OF RRN3
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批准号:7602042
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项目类别:
-
资助金额:$0.54万
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财政年份:2007
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负责人:LAWRENCE I ROTHBLUM
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依托单位:
Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
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批准号:7509303
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项目类别:
-
资助金额:$31.82万
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财政年份:2006
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
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批准号:7216335
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项目类别:
-
资助金额:$4.11万
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财政年份:2006
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
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批准号:7102194
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项目类别:
-
资助金额:$36.19万
-
财政年份:2006
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Ribosome Biogenesis: A Molecular Checkpoint for Cardiac Hypertrophy
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批准号:7393796
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项目类别:
-
资助金额:$35.56万
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财政年份:2006
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Protein interactions and initiation by RNA polymerase I
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批准号:7112944
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项目类别:
-
资助金额:$22.25万
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财政年份:2005
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负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Protein interactions and initiation by RNA polymerase I
-
批准号:7486224
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项目类别:
-
资助金额:$21.67万
-
财政年份:2005
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Protein interactions and initiation by RNA polymerase I
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批准号:7277122
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项目类别:
-
资助金额:$21.67万
-
财政年份:2005
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
Protein interactions and initiation by RNA polymerase I
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批准号:6968735
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项目类别:
-
资助金额:$21.83万
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财政年份:2005
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负责人:LAWRENCE I ROTHBLUM
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依托单位:
REGULATION OF RRNA SYNTHESIS DURING CARDIAC HYPERTROPHY
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批准号:2223823
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项目类别:
-
资助金额:$21.11万
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财政年份:1992
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负责人:LAWRENCE I ROTHBLUM
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依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
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批准号:2184460
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项目类别:
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资助金额:$16.47万
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财政年份:1992
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负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
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批准号:6018879
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项目类别:
-
资助金额:$15.44万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
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批准号:2734723
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项目类别:
-
资助金额:$16.93万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
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批准号:2444814
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项目类别:
-
资助金额:$16.49万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
-
批准号:2184458
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项目类别:
-
资助金额:$15.05万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
-
批准号:6324180
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项目类别:
-
资助金额:$2.36万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
REGULATION OF RRNA SYNTHESIS DURING CARDIAC HYPERTROPHY
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批准号:3366871
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项目类别:
-
资助金额:$21.74万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
REGULATION OF RRNA SYNTHESIS DURING CARDIAC HYPERTROPHY
-
批准号:2223822
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项目类别:
-
资助金额:$20.45万
-
财政年份:1992
-
负责人:LAWRENCE I ROTHBLUM
-
依托单位:
TRANSCRIPTION OF RAT RIBOSOMAL DNA
-
批准号:2184457
-
项目类别:
-
资助金额:$16.13万
-
财政年份:1992
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负责人:LAWRENCE I ROTHBLUM
-
依托单位:
海外基金