Modulating Calcineurin Signaling Pathways in Muscle

调节肌肉中的钙调神经磷酸酶信号通路

• 批准号: 7822352
• 负责人: Beverly A Rothermel
• 金额: $ 1.63万
• 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: 2009-06-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822352
• 关键词: A Mouse; Address; Apoptotic; Area; Art Therapy; Binding; Biological; Biology; Calcineurin; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Death; Cells; Cessation of life; Clinical; Communities; Complex; Country; Development; Epidemic; Family; Figs - dietary; Genes; Genetic Screening; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Hypoxia; In Vitro; Infarction; Laboratories; Link; MDM2 gene; Molecular; Mus; Muscle; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neonatal; Oxidative Stress; Pathology; Pathway interactions; Physiological; Play; Prevalence; Process; Property; Protein Family; Protein Isoforms; Protein phosphatase; Proteins; Rattus; Regulation; Reperfusion Therapy; Research Design; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Stress; System; TP53 gene; Techniques; Testing; Transgenic Mice; Ubiquitin; United States; Vascular Endothelial Growth Factors; Work; angiogenesis; base; biological adaptation to stress; cullin 4A; effective therapy; enhancer binding protein; heart disease prevention; in vivo; insight; killings; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; oxidative damage; pressure; prevent; public health relevance; research study; response; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Hypertrophic and ischemic heart disease has reached epidemic proportions both in this country and globally. As a result, there is urgent need for new and more effective therapies. Calcineurin is a calcium-regulated protein phosphatase that promotes hypertrophic growth and remodeling of the heart under stress. Our laboratory identified a family of proteins recently renamed RCANs for Regulators of Calcineurin. We demonstrated that RCANs bind to and inhibit calcineurin activity in heart and skeletal muscle. We showed that increased expression of RCAN1 in transgenic mice protects the heart from a wide variety of stresses by blunting both hypertrophic growth and the progression to heart failure after myocardial infarction. Strategies to increase the expression or activity of RCANs in the heart may therefore have clinical value for the treatment and prevention of heart disease. This proposal is a competitive renewal of our RO1 entitled "Modulating Calcineurin Signaling Pathways in Muscle." Accomplishment of our initial goals has contributed significantly toward understanding RCAN's regulation of calcineurin and its biological significance. Our findings have taken us in exciting new directions that may link regulation of calcineurin by RCAN1 to hypoxic or oxidative stress responses. Importantly, we, and others, have recently found that the area of infarct is larger in the hearts of mice lacking RCAN1 after ischemic-reperfusion (I/R). Together these findings suggest that RCAN1 can both limit hypertrophic growth in response to pressure overload and reduce damage from I/R. Our new goals address important questions that have grown out of these findings. Specific Aim 1: To determine the role of the CAATT/enhancer binding protein beta (C/EBPb) in regulating RCAN1.4 expression and test its involvement in hypertrophic remodeling of the heart. In this section we will test the ability of C/EBPb, which is activated in response to cardiac hypoxia, to control RCAN1.4 expression and determine whether C/EBPb activity influences calcineurin signaling or cardiac hypertrophy. Specific Aim 2: To define interactions of RCAN1 isoforms with the ubiquitin/proteasome system and to test whether these contribute isoform-specific functions in the setting of cardiomyocyte hypertrophy. We have identified two different classes of ubiquitin ligase complexes that interact specifically with one RCAN1 isoform but not the other. A cullin 4A E3 ligase complex (Cul4A) interacts with RCAN1.4, whereas the Von Hippel-Lindau factor (VHL), an integral component of hypoxic responses, interacts with RCAN1.1. Specific Aim 3: To define mechanisms through which RCAN1 protects cardiomyocytes from oxidative damage. In this portion of the proposal we will use both in vitro and in vivo techniques to test whether RCAN1 protects cardiac myocytes from oxidative damage and assess the involvement of mechanisms studied in Aims 1 and 2 in this process. These studies are designed to clarify the mechanism, regulation and physiological role of RCAN1 and create the basis for novel therapeutic approaches to the treatment and prevention of heart disease. PUBLIC HEALTH RELEVANCE Cardiovascular disease leading to heart failure is the leading cause of death in the Unites States and is increasing in prevalence despite the application of state-of-the-art therapies. There is a clear need for the development of new therapies. This proposal will provide important information regarding a family of endogenous proteins that protect the heart called Regulators of Calcineurin (RCANs). These studies will clarify the mechanism, regulation and physiological role of RCAN proteins and create the basis for novel therapeutic approaches to regulating calcineurin, a protein involved in the progression of a wide range of pathologies including heart disease and Alzheimers.

描述（由申请人提供）：肥厚性和缺血性心脏病在美国和全球已达到流行病的程度。因此，迫切需要新的和更有效的治疗方法。钙调神经磷酸酶是一种钙调节的蛋白磷酸酶，在压力下促进心脏肥大生长和重塑。我们的实验室确定了一个家族的蛋白质最近更名为RCAN钙调磷酸酶的调节。我们证明了RCAN结合并抑制心脏和骨骼肌中的钙调磷酸酶活性。我们发现，转基因小鼠中RCAN 1表达的增加通过减缓心肌梗死后的肥厚性生长和心力衰竭的进展来保护心脏免受各种各样的应激。因此，增加心脏中RCAN的表达或活性的策略可能对治疗和预防心脏病具有临床价值。这项提案是我们的RO 1的竞争性更新，题为“调节肌肉中的钙调神经磷酸酶信号通路”。“我们最初目标的实现为理解RCAN对钙调神经磷酸酶的调节及其生物学意义做出了重大贡献。我们的研究结果使我们进入了一个令人兴奋的新方向，可能将RCAN 1对钙调神经磷酸酶的调节与缺氧或氧化应激反应联系起来。重要的是，我们和其他人最近发现，缺血再灌注（I/R）后缺乏RCAN 1的小鼠心脏的梗死面积更大。总之，这些研究结果表明，RCAN 1既可以限制响应压力过载的肥大性生长，又可以减少I/R造成的损伤。我们的新目标解决了从这些发现中产生的重要问题。具体目标1：确定CAATT/增强子结合蛋白β（C/EBPb）在调节RCAN1.4表达中的作用，并检测其在心脏肥厚性重塑中的作用。在本节中，我们将测试C/EBPb的能力，这是激活响应心脏缺氧，以控制RCAN1.4的表达，并确定C/EBPb的活动是否影响钙调磷酸酶信号传导或心脏肥大。具体目标二：确定RCAN 1亚型与泛素/蛋白酶体系统的相互作用，并检测这些亚型是否在心肌细胞肥大中发挥特异性功能。我们已经确定了两种不同类型的泛素连接酶复合物的相互作用，特别是与一个RCAN 1亚型，但不是其他。cullin 4A E3连接酶复合物（Cul 4A）与RCAN 1.4相互作用，而缺氧反应的组成部分Von Hippel-Lindau因子（VHL）与RCAN 1.1相互作用。具体目标3：确定RCAN 1保护心肌细胞免受氧化损伤的机制。在这部分的提案中，我们将使用体外和体内技术来测试RCAN 1是否保护心肌细胞免受氧化损伤，并评估目标1和2中研究的机制在这一过程中的参与。这些研究旨在阐明RCAN 1的机制，调节和生理作用，并为治疗和预防心脏病的新治疗方法奠定基础。公共卫生相关性导致心力衰竭的心血管疾病是美国的主要死亡原因，尽管应用了最先进的治疗方法，但其患病率仍在上升。显然需要开发新的治疗方法。该提案将提供有关保护心脏的内源性蛋白质家族的重要信息，称为钙调磷酸酶调节剂（RCAN）。这些研究将阐明RCAN蛋白的机制、调节和生理作用，并为调节钙调神经磷酸酶的新治疗方法奠定基础，钙调神经磷酸酶是一种参与包括心脏病和阿尔茨海默病在内的多种病理进展的蛋白质。