Regulation and function of mitochondrial calcium uniporter in the heart

心脏线粒体钙单转运蛋白的调节和功能

基本信息

批准号：
10705327
负责人：
Wang Wang
金额：
$ 73.56万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705327
关键词：
Acute Adult Biology Birth CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cardiac Cardiac Myocytes Cause of Death Cell Death Cell Survival Cell physiology Cells Cessation of life Chronic stress Complex Conflict (Psychology)Couples Coupling Data Energy Metabolism Enzymes Exhibits Functional disorder Gene Expression Genetic Transcription Goals Healthcare Heart Heart Diseases Heart Hypertrophy Heart Mitochondria Heart failure Homeostasis Impairment Knock-out Knockout Mice Knowledge Lymphocyte Mediating Medicine Metabolic Mitochondria Mitochondrial Proteins Molecular Mus Myocardial dysfunction Nuclear Translocation Oxidation-Reduction Oxidative Stress Pathologic Pathway interactions Performance Perinatal Phenotype Play Proteins Pump Reactive Oxygen Species Regulation Renaissance Reperfusion Injury Reporting Research Respiration Role Seminal Signal Transduction Site Stress Structure of thyroid parafollicular cell Testing Tissues Transcriptional Regulation Treatment Failure Uncertainty United States Up-Regulation base beta-adrenergic receptor calcium uniporter calmodulin-dependent protein kinase II disease phenotype druggable target gain of function loss of function mitochondrial permeability transition pore novel pressure prevent sensor tool uptake

项目摘要

Summary Heart failure is the leading cause of death and a huge burden on health care in the United States. Recently, impaired energy metabolism has emerged as a key contributor to the failure of the heart’s pumping function, and new breakthroughs in metabolic research and mitochondrial biology have been reported. One of the key mechanisms for regulating mitochondrial function in the beating heart is calcium uptake through mitochondrial calcium uniporter (MCU). Surprisingly, MCU knockout mice exhibited normal phenotype, heart performance and mitochondrial function, indicating that MCU is dispensable in the normal heart. Pathological significance of MCU or mitochondrial calcium in the hypertrophic and failing heart is also elusive and highly debated. Finally, how MCU gene expression is regulated in the heart remains unexplored. These gaps in knowledge diminished the initial excitement ignited by the discovery of the molecular identity of MCU. Our promising preliminary results show that MCU expression is high in perinatal heart and in the chronically stressed adult heart via transcriptional regulation by calcium-calmodulin dependent protein kinase II δB (CaMKIIδB). Loss-of-function and gain-of- function approaches reveal that MCU plays a compensatory role in heart hypertrophy and dysfunction through modulating cytosolic calcium and cell death pathways. Unexpectedly, knockout MCU during the perinatal stage worsened pressure overload-induced heart dysfunction in adult mice. Based on these results, we hypothesize that MCU expression is strategically enhanced in the perinatal heart and in the stressed adult heart to ameliorate pathological heart remodeling. We will test this hypothesis in three Specific Aims. We will determine the molecular mechanisms by which CaMKIIδB regulates MCU gene expression. We will answer why cardiac hypertrophy and dysfunction are alleviated by MCU upregulation but aggravated by MCU inhibition. Furthermore, we will investigate the regulation of MCU in perinatal heart and how MCU limits pressure overload-induced dysfunction in the adult heart. Results of this study will depict a full mechanism by which MCU gene expression is fine tuned in the heart. This study also aims to uncover novel roles of MCU in perinatal heart and in the hypertrophic adult heart that counteract cardiac remodeling induced by multiple stresses.

概括最近，心力衰竭是美国的首要死亡原因，也是医疗保健的巨大负担。能量代谢受损已成为心脏泵血功能衰竭的一个关键因素，并且代谢研究和线粒体生物学的新突破已被报道，其中关键之一。调节跳动心脏中线粒体功能的机制是通过线粒体吸收钙令人惊讶的是，MCU 敲除小鼠表现出正常的表型、心脏功能和功能。线粒体功能，表明MCU在正常心脏中是可有可无的。肥厚和衰竭心脏中的线粒体钙也难以捉摸并且备受争议。 MCU 基因表达在心脏中的调节仍未得到探索。 MCU 分子特性的发现激发了我们最初的兴奋。表明 MCU 通过转录在围产期心脏和长期应激的成年心脏中表达较高钙调蛋白依赖性蛋白激酶 II δB (CaMKIIδB) 的功能丧失和增强的调节。功能方法表明，MCU 通过以下方式在心脏肥大和功能障碍中发挥代偿作用：意想不到的是，在围产期敲除 MCU。加剧了成年小鼠压力超负荷引起的心脏功能障碍根据这些结果，我们陷入了困境。 MCU 表达在围产期心脏和应激的成人心脏中得到战略性增强，以改善我们将在三个具体目标中检验这一假设。 CaMKIIδB 调节 MCU 基因表达的分子机制我们将回答为什么心脏。 MCU 上调可减轻肥大和功能障碍，但 MCU 抑制会加剧肥大和功能障碍。我们将研究MCU对围产期心脏的调节以及MCU如何限制压力超负荷引起的这项研究的结果将描述 MCU 基因表达的完整机制。这项研究还旨在揭示 MCU 在围产期心脏和心脏中的新作用。肥大的成人心脏可以抵消多种应激引起的心脏重塑。