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

STIM1 and its role in regulating cardiac metabolism

STIM1及其在心脏代谢中的调节作用

基本信息

批准号：
10592268
负责人：
JOHN C CHATHAM
金额：
$ 54.66万
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：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592268
关键词：
Acceleration Adult Adverse effects Age Amino Acids Attenuated Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiovascular Diseases Cell membrane Cells Development Diabetes Mellitus Dilated Cardiomyopathy Disease Elements Energy Metabolism Etiology Eukaryotic Cell Event Exhibits Fasting Fatty Acids Foundations Functional disorder GLUT 4 protein Genetic Transcription Glucose Glycolysis Goals Heart Heart Diseases Heart failure Homeostasis Hormones Hypertrophy Impairment Incidence Ketone Bodies Knockout Mice Knowledge Lipids Metabolic Metabolism Mitochondria Molecular Pathology Pathway interactions Phosphorylation Physiological Play Post-Translational Protein Processing Production Prognosis Proteins Pyruvate Quality Control Recurrence Regulation Reporting Repression Role STIM1 gene Signal Pathway Signal Transduction Survival Rate System Testing Up-Regulation Workload calcium metabolism diabetic cardiomyopathy effective therapy feeding flexibility glucose metabolism heart function heart metabolism improved insight insulin signaling metabolic phenotype mortality novel therapeutics oxidation pressure pyruvate dehydrogenase response restoration

项目摘要

Mortality rates associated with cardiovascular disease have decreased significantly; however, the incidence of heart failure continues to grow and 5-year survival rates remain at ~50%, underscoring the need to improve our knowledge of the molecular underpinnings of this disease. The heart requires a high level of metabolic flexibility to enable it to continuously adapt to changing workload demands throughout the day. Substrate availability and hormone levels also fluctuate with fasting/feeding cycles, further demanding cardiac metabolic flexibility. Loss of cardiac metabolic flexibility is a recurrent feature of cardiac disease, observed during hypertrophy, heart failure and diabetic cardiomyopathy. Similarly, dysregulation of Ca2+ homeostasis is a common element underlying the etiology of many cardiac diseases. Calcium is an established regulator of cardiac metabolism and mitochondrial function, through direct allosteric interactions, posttranslational modifications, and transcriptional events. However, despite established roles of Ca2+ in regulating cardiac energy metabolism, the specific Ca2+ handling pathways involved are not well characterized and their role in maintaining metabolic flexibility is not known. STromal Interaction Molecule-1 (STIM1) is a ubiquitously expressed and highly evolutionarily conserved protein located in the ER/SR that is responsible for regulating diverse Ca2+ signaling pathways in non-excitable cells and is recognized as a core element of all mammalian Ca2+ signaling systems. Despite discovery of STIM1 in the heart approximately 20 years ago, our knowledge about the physiological role of STIM1 in adult cardiomyocytes remains unclear and controversial. We recently reported that cardiomyocyte deletion of STIM1 (crSTIM1-KO) precipitates contractile dysfunction and dilated cardiomyopathy by 36 weeks of age. In young crSTIM1-KO mice prior to onset of contractile dysfunction there was impaired glucose metabolism and insulin signaling combined with increased lipid accumulation and an upregulation of lipogenic proteins. This metabolic phenotype is very similar to the cardiac metabolic signature observed during diabetes, a well characterized example of metabolic inflexibility. Collectively, these observations have led to the hypothesis that STIM1 is a previously unrecognized regulator of cardiac metabolism and mitochondrial function and that decreased STIM1 contributes to the adverse effects of diabetes on the heart. To test this hypothesis, we will 1) Define fully the extent to which STIM1 regulates cardiac metabolism; 2) Establish the mechanisms by which STIM1 influences mitochondrial function in the heart and 3) Determine how diabetes regulates STIM1 levels and whether loss of STIM1 contributes to the adverse effects of diabetes on the heart. The successful completion of this proposal will provide significant new insights into the role of STIM1 in regulating cardiac metabolism and mitochondrial function and provide the foundation for improved understanding regarding the contribution of STIM1 dysregulation to cardiac metabolic inflexibility and contractile dysfunction during disease states.

与心血管疾病相关的死亡率显著下降;然而，心力衰竭持续增长，5年生存率保持在50%左右，强调需要改善我们对这种疾病分子基础的了解心脏需要高水平的代谢灵活性，使其能够不断适应全天不断变化的工作量需求。底物可用性和激素水平也会随着禁食/喂养周期而波动，进一步要求心脏代谢灵活性心脏代谢灵活性的丧失是心脏病的复发特征，心脏肥大心力衰竭和糖尿病性心肌病类似地，Ca 2+稳态的失调是这是许多心脏病病因学的共同因素。钙是一种公认的调节剂，心脏代谢和线粒体功能，通过直接变构相互作用，翻译后修饰和转录事件。然而，尽管Ca 2+在调节心脏功能中的作用已经确立，能量代谢，涉及的特定Ca 2+处理途径没有得到很好的表征，在维持代谢灵活性方面的作用尚不清楚。STromal相互作用分子-1（STIM 1）是一种在ER/SR中广泛表达且高度进化保守的蛋白质，负责调节非兴奋细胞中的多种Ca 2+信号通路，并被认为是所有哺乳动物Ca 2+信号系统。尽管大约20年前在心脏中发现了STIM 1，我们对STIM 1在成年心肌细胞中的生理作用的认识仍然不清楚，争议我们最近报道，心肌细胞缺失STIM 1（crSTIM 1-KO）可促进心肌收缩，功能障碍和扩张型心肌病。在crSTIM 1-KO小鼠中，收缩功能障碍，葡萄糖代谢受损，胰岛素信号传导增加，脂质积累和脂肪生成蛋白的上调。这种代谢表型非常类似于在糖尿病期间观察到的心脏代谢特征，这是代谢稳定性的良好表征的实例。总的来说，这些观察结果导致了一个假设，即STIM 1是一种以前未被认识到的心脏代谢和线粒体功能的调节剂，减少STIM 1有助于糖尿病对心脏的不良影响为了检验这个假设，我们将1）充分定义 STIM 1调节心脏代谢的机制; 2）建立STIM 1影响心脏代谢的机制 3）确定糖尿病如何调节STIM 1水平以及是否存在心肌线粒体功能。 STIM 1有助于糖尿病对心脏的不良影响。成功完成这一提案将为STIM 1在调节心脏代谢和线粒体中的作用提供重要的新见解。发挥作用，并为更好地了解STIM的贡献奠定基础1 在疾病状态期间，心脏代谢稳定性和收缩功能障碍的失调。