STIM1 and its role in regulating cardiac metabolism

STIM1及其在心脏代谢中的调节作用

• 批准号: 10371868
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371868
• 关键词: Adult; Adverse effects; Age; Amino Acids; Attenuated; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cell membrane; Cells; 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; cardiogenesis; 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

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着降低。但是，发生率 心力衰竭持续增长，5年的存活率保持〜50％，强调了改善的需求 我们对这种疾病的分子基础的了解。心脏需要高水平 代谢灵活性使其能够全天不断适应不断变化的工作量需求。 底物的可用性和激素水平也随空腹/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，观察到 在肥大，心力衰竭和糖尿病心肌病中。同样，CA2+稳态的失调是 许多心脏病病因的基础的共同元素。钙是既定的调节剂 心脏代谢和线粒体功能，通过直接变构相互作用，翻译后 修改和转录事件。但是，尽管CA2+在调节心脏方面已确立了作用 能量代谢，涉及的特定CA2+处理途径的表征没有很好，它们 尚不清楚维持代谢柔韧性的作用。基质相互作用分子1（stim1）是一个 普遍表达的ER/SR中的高度进化保守的蛋白质负责 调节非驱动细胞中不同的Ca2+信号传导途径，并被认为是所有人的核心元素 哺乳动物CA2+信号系统。尽管大约20年前在心脏中发现了Stim1，但 我们对STIM1在成人心肌细胞中生理作用的知识尚不清楚，并且 有争议的。我们最近报道说，刺激的心肌细胞缺失（CRSTIM1-KO）会沉淀 功能障碍和扩张性心肌病在36周龄。在年轻的crstim1-ko小鼠发作之前 收缩功能障碍存在受损的葡萄糖代谢和胰岛素信号传导，并增加 脂质积累和脂肪生成蛋白的上调。这种代谢表型与 在糖尿病期间观察到的心脏代谢特征，这是代谢不灵活的一个特征的例子。 总的来说，这些观察结果导致了一个假设，即STIM1是先前未知的 心脏代谢和线粒体功能的调节剂，降低stim1有助于 糖尿病对心脏的不利影响。为了检验这一假设，我们将1）完全定义 刺激了心脏代谢； 2）建立STIM1影响的机制 心脏中的线粒体功能和3）确定糖尿病如何调节Stim1水平以及是否丧失 STIM1导致糖尿病对心脏的不利影响。该提案的成功完成 将为STIM1在调节心脏代谢和线粒体中的作用提供重要的新见解 功能并为提高刺激的贡献的理解提供基础 在疾病状态下，对心脏代谢的不灵活性和收缩功能障碍的失调。