A novel anti-hypertrophic pathway in the heart

心脏中一种新型的抗肥厚途径

• 批准号: 7739264
• 负责人: Peifeng Li
• 金额: $ 23.49万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739264
• 关键词: Accounting; Animal Model; Antioxidants; Attenuated; Bioinformatics; Biological; Boxing; Calcineurin; Cardiac; Cardiac Myocytes; Cell Volumes; Cell model; Collagen; Deposition; Development; Electric Conductivity; Enzymes; Equilibrium; Family; Fibroblasts; Gene Expression; Genetic Translation; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Lead; MLLT7 gene; Mediating; Messenger RNA; MicroRNAs; Molecular; Muscle Contraction; Myocardium; NADPH Oxidase; Nucleotides; Pathway interactions; Physiological; Play; Production; Proteins; Reactive Oxygen Species; Regulation; Regulator Genes; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Sudden Death; Testing; Transcriptional Regulation; Work; catalase; heart dimension/size; interstitial; meetings; member; novel; prevent; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Summary Cardiac hypertrophy occurs in response to a variety of physiological and pathophysiological conditions. However, sustained cardiac hypertrophy plays an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. Although multiple signaling pathways have been shown to be implicated in the development of hypertrophy, it is poorly understood regarding the anti-hypertrophic pathways in the heart. FOXO3a is a transcriptional factor. Most recent studies show that it can negatively regulate cardiac hypertrophy. Cardiac hypertrophy can be mediated by the signaling molecules including reactive oxygen species (ROS). The cellular equilibrium of ROS is regulated by the antioxidant enzymes such as catalase. Our preliminary studies showed that FOXO3a is able to upregulate the expression of catalase in cardiomyocytes. Furthermore, knockdown of FOXO3a led to an increased level of ROS and cardiomyocyte hypertrophy. Administration of the antioxidant could attenuate hypertrophy upon FOXO3a knockdown. These observations lead us to hypothesize that "the regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart''. We will test this through studies under the following specific aims. Aim-1 will determine whether FOXO3a regulates hypertrophy by targeting catalase in the cellular model. Aim-2 will elucidate whether FOXO3a-catalase pathway is activated in the animal model. Aim-3 will characterize whether FOXO3a-catalase pathway is regulated by miRNAs. This proposed study will not only help us understand the role of FOXO3a-catalase in regulating cardiac hypertrophy, but could lead to further studies to explore the beneficial effect of this pathway as a biological target for the interventional treatment of maladaptive hypertrophy as well as heart failure. PUBLIC HEALTH RELEVANCE: Sustained cardiac hypertrophy has been proved to play an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. This project is to characterize whether the transcriptional regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart. The successful completion of project will provide important information for exploring the beneficial effects of this pathway in controlling hypertrophy as well as heart failure.

描述（由申请人提供）：总结心脏肥大是响应于多种生理和病理生理条件而发生的。然而，持续的心脏肥大对于导致心力衰竭或猝死的适应不良心脏重塑的发展起着重要作用。尽管多种信号传导途径已被证明与肥大的发展有关，但人们对心脏的抗肥大途径知之甚少。 FOXO3a 是一种转录因子。最近的研究表明它可以负面调节心脏肥大。心脏肥大可以由包括活性氧（ROS）在内的信号分子介导。 ROS 的细胞平衡由过氧化氢酶等抗氧化酶调节。我们的初步研究表明，FOXO3a 能够上调心肌细胞中过氧化氢酶的表达。此外，FOXO3a 的敲低导致 ROS 水平升高和心肌细胞肥大。施用抗氧化剂可以减轻 FOXO3a 敲低后的肥大。这些观察结果使我们假设“FOXO3a对过氧化氢酶的调节构成了心脏中的抗肥厚途径”。我们将通过以下具体目标的研究来测试这一点。Aim-1将确定FOXO3a是否通过在细胞模型中靶向过氧化氢酶来调节肥厚。Aim-2将阐明FOXO3a-过氧化氢酶途径在动物模型中是否被激活。Aim-3将表征是否 FOXO3a-过氧化氢酶途径受 miRNA 调节。这项拟议的研究不仅将帮助我们了解 FOXO3a-过氧化氢酶在调节心脏肥大中的作用，而且可能导致进一步的研究，探索该通路作为介入治疗适应不良肥厚和心力衰竭的生物靶点的有益作用。公众健康相关性：持续的心脏肥大已被证明在以下疾病的发生中发挥着重要作用： 适应不良的心脏重塑导致心力衰竭或猝死。该项目旨在表征 FOXO3a 对过氧化氢酶的转录调节是否构成心脏中的抗肥厚途径。该项目的成功完成将为探索该途径在控制肥厚和心力衰竭方面的有益效果提供重要信息。