Transcription Programming in Cardiac Growth

心脏生长中的转录编程

基本信息

批准号：
7665568
负责人：
Nanette Hahr Bishopric
金额：
$ 38.25万
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/7665568
关键词：
Acetylation Acetyltransferase Affect Age Alleles American Calcineurin Cardiac Cardiac Myocytes Cell Culture Techniques Cell Survival Cessation of life Clinical Data 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 Positioning Attribute Protein Acetylation Proteins 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 common treatment in vivo loss of function mortality multicatalytic endopeptidase complex myocyte-specific enhancer-binding factor 2 overexpression p300/CBP-Associated Factor postnatal pressure prevent programs promoter protein expression public health relevance 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）：我们的实验室已确定乙酰转移酶 p300 在调节出生后心肌细胞生长中发挥关键作用。我们发现乙酰转移酶 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生长能力直接且化学计量相关，因此即使 p300 水平的微小变化也会对心肌细胞生长产生很大影响。单个 p300 等位基因的缺失足以损害心脏随着年龄的增长和对压力超负荷的反应。我们还发现 p300 在缺血和氧化应激过程中也会被快速诱导，并传递细胞保护信号。因此，p300 的快速诱导似乎是一种关键的心脏应激反应。尽管动态控制 p300 水平可能很重要，但我们对应激期间控制 p300 mRNA 和蛋白质水平上调的机制一无所知。基于这些发现，我们假设 (1) 在心脏应激期间“立即早期”、心肌细胞自主诱导 p300 是其他已确定的效应物（包括钙调神经磷酸酶）诱导心脏肥大的节点事件，并且 (2) 诱导p300 的表达是由一系列信号响应转录前和转录后事件介导的，包括磷酸化、乙酰化、泛素化和消除抑制非编码RNA。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的影响。我们将进行心脏特异性 p300 和 CBP 删除，以确定这些蛋白质在肥大中是否具有独特的或肌细胞自主的作用。最后，我们将在 p300tg 和 HDAC5 或 9 缺陷小鼠之间，以及 p300 缺陷和钙调神经磷酸酶 tg 小鼠之间进行遗传互补实验。这些实验将明确确定 p300 相对于 II 类组蛋白脱乙酰酶和钙调磷酸酶在体内肥大信号转导中的位置。公共卫生相关性超过三百万美国人患有心力衰竭。尽管临床取得了重大进展，但死亡率仍然极高；首次心力衰竭发作后 5 年内存活率不足 40%。心脏在衰竭前数月或数年开始肥大或扩大。肥大本身是死亡的独立危险因素。目前还没有治疗方法可以预防肥厚或延缓其进展为心力衰竭。通过揭示肥厚的特定分子信号，我们的研究可能有助于为这些常见和致命形式的心脏病找到新的治疗方法。