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触发心脏的肥厚性生长，这显着增加了失败的风险和恶性节律障碍。相比之下，响应生理需求的心脏的生长是适应性的，并且与不良频谱无关。最近，我们表明FOXO转录因子在调节心肌细胞生长中起关键作用。相反，心脏能够在各种临床相关的情况下（例如机械支持）大大收缩。肌肉萎缩是一种需要激活泛素连接酶的活跃的，需要能量的过程。 FOXO转录控制着这种“阳性蛋白”的反应。因此，FOXO因子位于多种形式的心脏可塑性的Nexus。在这里，我们提出了对心脏生长和重塑中FOXO信号传导的全面分析。我们的中心假设是FOXO转录因子是心脏增长的负调节剂。我们建议在三种主要的心脏重塑形式中定义和操纵这些分子的作用：1）由血液动力学胁迫造成的病理肥大； 2）运动的生理肥大； 3）心室卸载的心脏萎缩。目标1：测试心脏肥大期间FOXO转录因子的功能相关性。使用功能障碍和功能丧失策略，我们将以两种主要形式的心脏增长来定义和操纵FOXO的作用，即。病理和生理肥大。目标2：测试心脏萎缩期间FOXO转录因子的功能相关性。使用异位心脏移植的模型，我们将在心室卸载中定义和操纵FOXO的作用。目标3：定义和操纵机制，FOXO影响钙调神经酶和AKT活动，分别是病理和生理肥大的两个关键介体。我们有证据表明，FoxO激活是抑制钙调神经信号传导的强大机制，这是导致病原心脏肥大的主要途径。相比之下，通过PI3K/AKT轴信号传导有助于生理心脏的生长，并且我们的数据表明FOXO能够激活AKT。在这里，我们将破译机制，使FOXO靶向这些主要的病理（钙调神经酶）和生理（AKT）心脏肥大的效应。公共卫生相关性：预计到2020年，心血管疾病被预计是全球死亡率的最常见原因。最近的研究表明，Foxo转录因子位于多种形式的心脏可塑性。通过确定它们在病理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。