Foxo: Negative Regulator of Cardiac Hypertrophy

Foxo：心脏肥大的负调节因子

• 批准号: 7806527
• 负责人: JOSEPH A HILL
• 金额: $ 39.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806527
• 关键词: Atrophic; Bed rest; Calcineurin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle Progression; Data; Disease; Employee Strikes; Exercise; Failure; Family; Gap Junctions; Genetic Transcription; Growth; Health; Heart; Heart Hypertrophy; Heart Transplantation; Heart failure; Heterotopic Transplantation; Human; Hypertension; Hypertrophy; Injury; Lead; Malignant - descriptor; Mechanics; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Muscular Atrophy; Myocardial; Organ; Pathogenesis; Pathway interactions; Physiological; Plastics; Play; Pregnancy; Process; Proteins; Reaction; Risk; Role; Signal Transduction; Skeletal Muscle; Source; State of Zero Gravity; Stimulus; Stress; Testing; Therapeutic; Travel; Ventricular; base; clinically relevant; forkhead protein; gain of function; hemodynamics; inhibitor/antagonist; insight; loss of function; member; mortality; novel strategies; novel therapeutics; prevent; protein degradation; public health relevance; response; stem; transcription factor; ubiquitin ligase; ventricular assist device

DESCRIPTION (provided by applicant): Disease-related stresses trigger hypertrophic growth of the heart that confers markedly increased risk of failure and malignant rhythm disturbance. By contrast, growth of the heart in response to physiological demand is adaptive and not associated with adverse sequalae. Recently, we have shown that FoxO transcription factors play a key role in regulating cardiac myocyte growth. Conversely, the heart is capable of shrinking substantially under a variety of clinically relevant circumstances, such as mechanical support. Muscle atrophy is an active, energy-requiring process requiring activation of ubiquitin ligases. FoxO transcription governs this "atrogene" response. Thus, FoxO factors are situated at the nexus of multiple forms of cardiac plasticity. Here, we propose a comprehensive analysis of FoxO signaling in cardiac growth and remodeling. Our central hypothesis is that FoxO transcription factors are negative regulators of cardiac growth. We propose to define and manipulate the role of these molecules in 3 major forms of cardiac remodeling: 1) pathological hypertrophy stemming from hemodynamic stress; 2) physiological hypertrophy of exercise; and 3) cardiac atrophy from ventricular unloading. Aim 1: To test the functional relevance of FoxO transcription factors during cardiac hypertrophy. Using gain-of-function and loss-of function strategies, we will define and manipulate the actions of FoxO in 2 major forms of cardiac growth, viz. pathological and physiological hypertrophy. Aim 2: To test the functional relevance of FoxO transcription factors during cardiac atrophy. Using a model of heterotopic cardiac transplantation, we will define and manipulate the actions of FoxO in the setting of ventricular unloading. Aim 3: To define and manipulate mechanisms whereby FoxO influences calcineurin and Akt activities, two key mediators of pathological and physiological hypertrophy, respectively. We have evidence that FoxO activation is a robust mechanism of suppressing calcineurin signaling, a major pathway leading to patho- logical cardiac hypertrophy. By contrast, signaling via the PI3K/Akt axis contributes to physiological heart growth, and we have data demonstrating that FoxO is capable of activating Akt. Here, we will decipher mechanisms whereby FoxO targets these major effectors of pathological (calcineurin) and physiological (Akt) cardiac hypertrophy. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases are predicted to be the most common cause of mortality worldwide by the year 2020. Recent studies reveal that FoxO transcription factors are situated at the nexus of multiple forms of cardiac plasticity. By determining their role in pathological cardiac growth and atrophy, we will take steps that may lead to novel strategies to prevent heart failure in humans.

描述(由申请人提供)：与疾病相关的压力会引发心脏肥大，从而显着增加衰竭和恶性心律失常的风险。相比之下，心脏对生理需求的反应是适应性的，与不良后遗症无关。最近，我们发现FoxO转录因子在调控心肌细胞生长中起着关键作用。相反，心脏能够在各种临床相关的情况下大幅收缩，例如机械支持。肌肉萎缩是一个活跃的、需要能量的过程，需要激活泛素连接酶。FOXO转录调控这一“再生基因”反应。因此，FOXO因子位于多种形式的心脏可塑性的连接点。在此，我们建议对FoxO信号在心脏生长和重构中的作用进行全面的分析。我们的中心假设是FoxO转录因子是心脏生长的负调控因子。我们建议定义和操纵这些分子在心脏重构的三种主要形式中的作用：1)血流动力学应激引起的病理性肥厚；2)运动引起的生理性肥厚；以及3)由心室卸载引起的心脏萎缩。目的1：探讨FoxO转录因子在心肌肥厚过程中的功能相关性。使用功能获得和功能丧失策略，我们将定义和操纵FoxO在心脏生长的两种主要形式中的作用，即。病理性和生理性肥大。目的：检测FoxO转录因子在心肌萎缩过程中的功能相关性。利用异位心脏移植模型，我们将定义和操纵FoxO在心室卸载设置中的作用。目的3：明确和调控FOXO影响钙调神经磷酸酶和Akt活性的机制，这两种酶分别是病理性和生理性肥大的关键介质。我们有证据表明，FoxO激活是抑制钙调神经磷酸酶信号的一种强有力的机制，钙调神经磷酸酶信号是导致病理性心肌肥大的主要途径。相比之下，通过PI3K/Akt轴的信号有助于心脏的生理性生长，我们有数据表明FoxO能够激活Akt。在这里，我们将破译FOXO针对病理性(钙调神经磷酸酶)和生理性(Akt)心肌肥厚的这些主要效应因子的机制。公共卫生相关性：到2020年，心血管疾病预计将成为全球最常见的死亡原因。最近的研究表明，FoxO转录因子位于多种形式的心脏可塑性的连接点。通过确定它们在病理性心脏生长和萎缩中的作用，我们将采取措施，可能导致新的策略来预防人类心力衰竭。