Transcription Programming in Cardiac Growth

心脏生长中的转录编程

• 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
• 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

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转移酶p300在调节出生后心肌细胞生长中的关键作用。我们发现乙酰转移酶p300在大多数或所有形式的心肌肥大中迅速上调。我们已经表明，p300的细胞浓度是直接和化学计量相关的心肌细胞的生长能力，这样，即使很小的变化，p300水平对心肌细胞的生长有很大的影响。单个p300等位基因的缺失足以损害随年龄增长的心脏生长和对压力超负荷的反应。我们还发现，p300也迅速诱导缺血和氧化应激，在那里它传达了细胞保护信号。因此，p300的快速诱导似乎是一个关键的心脏应激反应。尽管p300水平的动态控制可能很重要，但对压力期间p300 mRNA和蛋白水平上调的控制机制一无所知。基于这些发现，我们假设：（1）在心脏应激过程中，p300的“立即早期”、肌细胞自主诱导是由其他已鉴定的效应物（包括钙调神经磷酸酶）诱导心脏肥大的节点事件，以及（2）p300的诱导是由一系列信号响应性转录前和转录后事件介导的，包括磷酸化、乙酰化、泛素化，以及去除非编码RNA的抑制。我们建议测试乙酰化和磷酸化的调节剂的影响，以及特定的p300调节的miR的作用，在肥大信号传导过程中对p300的积累和乙酰转移酶活性的影响。我们将进行p300和CBP的心脏特异性缺失，以确定这些蛋白质是否在肥大中具有独特的或肌细胞自主的作用。最后，我们将在p300 tg和HDAC 5-或9-缺陷小鼠之间，以及在p300-缺陷和钙调磷酸酶tg小鼠之间进行遗传互补实验。这些实验将明确地确定p300相对于II类组蛋白脱乙酰酶和钙调神经磷酸酶在体内肥大信号转导中的位置。超过300万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;不到40%的人在首次心力衰竭发作后存活5年。心脏在衰竭前几个月或几年开始肥大或扩大。肥大本身是死亡的独立危险因素。目前还没有预防肥大或延缓其进展为心力衰竭的治疗方法。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的心脏病形式提供新的治疗方法。