权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

STIM1 mediated calcium entry: A new paradigm of metabolic regulation of cardiomyo

STIM1介导的钙进入：心肌代谢调节的新范例

基本信息

批准号：
8459907
负责人：
JOHN C CHATHAM
金额：
$ 17.55万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459907
关键词：
Adult Adverse effects Affect Anabolism Biological Biological Process Calcineurin Calcium Cardiac Cardiac Myocytes Cell membrane Cells Data Development Diabetes Mellitus Diagnosis Event G-Protein-Coupled Receptors Glucosamine Goals Growth Hearing problem Heart Heart Hypertrophy Heart failure Hexosamines Homeostasis Hyperglycemia Hypertension Hypertrophy Incidence Knockout Mice Knowledge Lead Left Ventricular Hypertrophy Link Mediating Mediator of activation protein Metabolic Modeling Modification Molecular Neonatal Nuclear Nuclear Envelope Nuclear Translocation Pathway interactions Phosphorylation Play Process Protein Family Proteins Quality of life Receptor Activation Regulation Reporting Risk Risk Factors Role STIM1 gene Serine Signal Pathway Signal Transduction Testing Threonine Time diabetic patient extracellular glucose metabolism improved in vivo insight loss of function mortality novel response voltage

项目摘要

DESCRIPTION (provided by applicant): Left ventricular hypertrophy (LVH) and diabetes are among the most potent risk factors for the development of heart failure; furthermore, the combination of diabetes with additional risk factors such as hypertension markedly increases the incidence of heart failure and decreases survival of those diagnosed with heart failure. A key event required for the initiation of hypertrophic signaling is the Ca2+ mediated activation of calcineurin and subsequent nuclear translocation of NFAT, which is currently believed to occur primarily via IP3 mediated Ca2+ release from the SR and nuclear envelope. However, in non-excitable cells, it is widely accepted that it is the subsequent influx of extracellular Ca2+ acros the plasma membrane, so called "store operated calcium entry" (SOCE) that is essential for activation of calcineurin and NFAT translocation. Recently STIM and Orai protein families have emerged as critical mediators of SOCE in non-excitable cells; however, little is known about the role of these proteins in the heart. The O-linked attachment of ss-N-acetyl-glucosamine (O-GlcNAc) to serine and threonine residues is rapidly emerging as a key mediator of numerous biological processes and has been linked to the adverse effects of diabetes on the heart and also to the regulation of SOCE. We have also recently shown that diabetes impairs cardiomyocyte hypertrophic signaling, at least in part by increased O-GlcNAc levels. Therefore, building on previous reports of SOCE in cardiomyocytes, integrating the recent knowledge of STIM and Orai proteins in mediating voltage- independent Ca2+ entry, combined with our knowledge of protein O-GlcNAcylation, we propose that STIM1-Orai1 facilitated non-voltage gated Ca2+ entry is a key mediator of Ca2+ signaling in adult cardiomyocytes and that O-GlcNAcylation of STIM1 inhibits its normal function thus providing a link between hyperglycemia and abnormal Ca2+-mediated signaling. To test this hypothesis we will pursue 2 specific aims: 1: Demonstrate that STIM1 mediates Ca2+ signaling in adult cardiomyocytes and plays a key role in development of cardiac hypertrophy in vivo; 2: Demonstrate that O-GlcNAc modification of STIM1 inhibits normal activation of STIM1-mediated Ca2+ signaling and contributes to impaired hypertrophic signaling seen in diabetes. We will use gain and loss of function approaches in isolated cardiomyocytes including a novel inducible cardiomyocyte restricted STIM1 knockout mouse to challenge the currently accepted paradigm of Ca2+ homeostasis in adult cardiomyocytes. The successful completion of this proposal will yield significant new insights into the fundamental mechanisms regulating Ca2+ signaling in the heart and establish for the first time a mechanistic link between glucose metabolism and Ca2+ homeostasis and identify novel molecular mediators of cardiac hypertrophy.

描述（由申请人提供）：左心室肥厚（LVH）和糖尿病是发生心力衰竭的最有力的危险因素；此外，糖尿病与高血压等其他危险因素相结合，会显着增加心力衰竭的发生率，并降低被诊断患有心力衰竭的患者的生存率。启动肥大信号所需的一个关键事件是 Ca2+ 介导的钙调神经磷酸酶激活和随后的 NFAT 核转位，目前认为这主要通过 IP3 介导的 Ca2+ 从 SR 和核膜释放而发生。然而，在非兴奋性细胞中，人们普遍认为细胞外 Ca2+ 随后穿过质膜流入，即所谓的“钙库操作钙内流”(SOCE)，这对于激活钙调神经磷酸酶和 NFAT 易位至关重要。最近，STIM 和 Orai 蛋白家族已成为非兴奋性细胞中 SOCE 的关键介质；然而，人们对这些蛋白质在心脏中的作用知之甚少。 ss-N-乙酰氨基葡萄糖 (O-GlcNAc) 与丝氨酸和苏氨酸残基的 O 型连接正迅速成为众多生物过程的关键介质，并与糖尿病对心脏的不利影响以及 SOCE 的调节有关。我们最近还发现，糖尿病至少部分是通过增加 O-GlcNAc 水平来损害心肌细胞肥大信号传导。因此，在心肌细胞中 SOCE 的先前报道的基础上，整合 STIM 和 Orai 蛋白在介导电压非依赖性 Ca2+ 内流方面的最新知识，结合我们对蛋白质 O-GlcNAcNAcylation 的了解，我们提出 STIM1-Orai1 促进非电压门控 Ca2+内流是成体心肌细胞中 Ca2+ 信号传导的关键介质，并且 O-GlcNAcNAcylation STIM1 抑制其正常功能，从而在高血糖和异常 Ca2+ 介导的信号传导之间提供联系。为了检验这一假设，我们将追求 2 个具体目标： 1：证明 STIM1 介导成体心肌细胞中的 Ca2+ 信号传导，并在体内心脏肥大的发展中发挥关键作用；图 2：证明 STIM1 的 O-GlcNAc 修饰可抑制 STIM1 介导的 Ca2+ 信号传导的正常激活，并导致糖尿病中出现的肥大信号传导受损。我们将在分离的心肌细胞中使用功能获得和丧失的方法，包括新型诱导型心肌细胞限制性 STIM1 敲除小鼠，以挑战目前公认的成体心肌细胞 Ca2+ 稳态范例。该提案的成功完成将为调节心脏 Ca2+ 信号传导的基本机制带来重要的新见解，并首次建立葡萄糖代谢和 Ca2+ 稳态之间的机制联系，并确定心脏肥大的新型分子介质。