Transcription Programming in Cardiac Growth

心脏生长中的转录编程

基本信息

批准号：
7533354
负责人：
Nanette Hahr Bishopric
金额：
$ 37.23万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2013-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533354
关键词：
Acetylation Acetyltransferase Affect Age Alleles American Calcineurin Cardiac Cardiac Myocytes Cell Survival Cessation of life Class Clinical Cultured Cells Data Disruption E1A-associated p300 protein EP300 gene Event Excision Functional RNA Gene Expression Gene Targeting Genetic Genetic Transcription Growth HDAC5 gene Half-Life Heart Heart Diseases Heart Hypertrophy Heart failure Histones Hypertrophy Laboratories Lead Life MAPK8 gene Mediating Messenger RNA MicroRNAs Mitogen-Activated Protein Kinase 3 Molecular Mus Muscle Cells Myocardium Nodal Oxidants Oxidative Stress Oxidative Stress Induction Peptide Signal Sequences Phenotype Phosphorylation Phosphotransferases Play Polymerase Chain Reaction Positioning Attribute Protein Acetylation Protein Overexpression Proteins Public Health Regulation Relative (related person)Reperfusion Injury Repression Risk Factors Role Signal Transduction Stress Testing Transcript Transgenes Transgenic Organisms Translations Ubiquitination Up-Regulation base biological adaptation to stress in vivo loss of function mortality multicatalytic endopeptidase complex myocyte-specific enhancer-binding factor 2 p300/CBP-Associated Factor postnatal pressure prevent programs promoter protein expression research study response ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Our laboratory has identified a critical role for the acetyltransferase p300 in the regulation of postnatal cardiac myocyte growth. We find that acetyltransferase p300 is rapidly upregulated in most or all forms of cardiac hypertrophy. We have shown that the cellular concentration of p300 is directly and stoichometrically related to cardiac myocyte growth capacity, such that even small changes in p300 levels have large effects on myocyte growth. Loss of a single p300 allele is sufficient to impair cardiac growth with age and in response to pressure overload. We also find that p300 is also rapidly induced during ischemic and oxidative stress, where it conveys a cytoprotective signal. The rapid induction of p300 thus appears to be a critical cardiac stress response. Despite the likely importance of dynamic control of p300 levels, nothing is known about the mechanisms that control upregulation of p300 mRNA and protein levels during stress. Based on these findings, we hypothesize that (1)"immediate-early", myocyte-autonomous induction of p300 during cardiac stress is the nodal event in the induction of cardiac hypertrophy by other identified effectors, including calcineurin, and that (2) induction of p300 is mediated by a sequence of signal-responsive pre- and post- transcriptional events, including phosphorylation, acetylation, ubiquitination, and removal of repression by non-coding RNAs. We propose to test the impact of modulators of acetylation and phosphorylation, and the role of specific p300-regulated miRs, on the accumulation and acetyltransferase activity of p300 during hypertrophic signaling. We will carry out cardiac-specific deletion of p300 and CBP to determine whether these proteins have distinct or myocyte-autonomous roles in hypertrophy. Finally, we will perform genetic complementation experiments between p300tg and HDAC5- or 9-deficient mice, and between p300-deficient and calcineurin tg mice. These experiments will definitively establish the position of p300 relative to the class II histone deacetylases and calcineurin in the transduction of hypertrophic signals in vivo. PUBLIC HEALTH RELEVANCE More than three million Americans are living with heart failure. Despite significant clinical advances, mortality remains extremely high; fewer than 40% will survive 5 years after their first episode of heart failure. The heart begins to undergo hypertrophy, or enlargement, months or years before it fails. Hypertrophy by itself is an independent risk factor for death. No therapy exists to prevent hypertrophy or delay its progression to heart failure. By revealing the specific molecular signals for hypertrophy, our studies may help lead to new treatments for these common and lethal forms of heart disease.

描述（由申请人提供）：我们的实验室已经确定了乙酰基转移酶P300在调节产后心肌细胞生长中的关键作用。我们发现，乙酰基转移酶P300在大多数或所有形式的心脏肥大中迅速上调。我们已经表明，p300的细胞浓度与心肌细胞的生长能力直接和化学相关，因此，即使p300水平的较小变化也会对肌细胞生长产生巨大影响。单个P300等位基因的损失足以随着年龄的增长和压力超负荷而损害心脏增长。我们还发现，p300在缺血性和氧化应激期间也迅速诱导，它传达了细胞保护信号。因此，p300的快速诱导似乎是临界心脏应力反应。尽管对p300水平的动态控制可能很重要，但在压力期间控制p300 mRNA和蛋白质水平的上调的机制尚无。 Based on these findings, we hypothesize that (1)"immediate-early", myocyte-autonomous induction of p300 during cardiac stress is the nodal event in the induction of cardiac hypertrophy by other identified effectors, including calcineurin, and that (2) induction of p300 is mediated by a sequence of signal-responsive pre- and post- transcriptional events, including phosphorylation, acetylation,泛素化和非编码RNA抑制作用。我们建议测试乙酰化和磷酸化调节剂的影响，以及特定p300调节的miR的作用，对肥大信号传导过程中p300的积累和乙酰转移酶活性。我们将对P300和CBP进行心脏特异性缺失，以确定这些蛋白质在肥大中是否具有独特的或心肌自主的作用。最后，我们将在P300TG和HDAC5或9缺陷小鼠之间以及P300缺陷型和钙调神经蛋白TG小鼠之间进行遗传互补实验。这些实验将确定建立p300相对于II类组蛋白脱乙酰基酶和钙调神经酶在体内肥厚信号中的位置。公共卫生相关性超过300万美国人患有心力衰竭。尽管临床进展很大，但死亡率仍然很高。在他们的心力衰竭第一集后5年，少于40％的人将生存。心脏开始发生肥大或扩大，在它失败之前。肥大本身是死亡的独立危险因素。没有治疗可以防止肥大或延迟其发展为心力衰竭。通过揭示肥大的特定分子信号，我们的研究可能有助于为这些常见和致命形式的心脏病提供新的治疗方法。