Modulating mitochondrial calcium in cardiac homeostasis and disease

调节心脏稳态和疾病中的线粒体钙

基本信息

批准号：
10683219
负责人：
Julia Chang Liu
金额：
$ 43.83万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683219
关键词：
Address Adrenergic Agents Adult Affect Animal Model Animals Basic Science Calcium Cardiac Cardiac Myocytes Cardiac health Cause of Death Cell Death Clinical Complex Data Diet Disease Disease Outcome Disease Progression EFRAC Echocardiography Fatty acid glycerol esters Fibrosis Functional disorder Future Gatekeeping Genes Goals Heart Heart Contractilities Heart failure Histology Homeostasis Hypertension Hypertrophy Impairment Knowledge Link Literature Maps Measures Mediating Metabolic syndrome Methodology Mission Mitochondria Modeling Molecular Multiprotein Complexes Mus Myocardial dysfunction NG-Nitroarginine Methyl Ester Obesity Operative Surgical Procedures Organism Outcome Outcome Assessment Outcomes Research Oxidative Stress Pathology Permeability Physiology Play Production Proteomics Public Health Pump Reporting Research Respiration Role Secondary to Signal Pathway Signal Transduction Sucrose Tamoxifen Testing Therapeutic Time Tissues United States National Institutes of Health Ventricular Function Work aorta constriction disability functional decline genetic manipulation glucose tolerance heart function improved in vivo innovation interest mitochondrial permeability transition pore mouse model novel preservation pressure protein complex protein expression response therapeutic development therapy development tool uptake

项目摘要

Project Summary/Abstract A leading cause of death worldwide, heart failure is often linked to deficits in energy production in mitochondria. Mitochondrial uptake of cytosolic Ca2+ plays a critical role in matching energy production to demand by stimulating ATP production. However, mitochondrial Ca2+ in excess can lead to permeability transition pore opening and potentially cell death. Animal models of heart failure more closely akin to heart failure with reduced ejection fraction (HFrEF) are linked to increased mitochondrial Ca2+ in some studies and decreased mitochondrial Ca2+ in others; even less is known regarding the role of mitochondrial Ca2+ in heart failure with preserved ejection fraction (HFpEF). With the long-term goal of helping to develop therapies to limit or restore mitochondrial Ca2+ when appropriate to improve clinical outcomes in HFrEF and HFpEF, this application will map out the contribution of increased and decreased mitochondrial Ca2+ to cardiac dysfunction in homeostasis and in mouse models of pressure overload and high fat/high sucrose diet with L-NAME. Tamoxifen-inducible cardiac-specific deletion of Micu1, the gene encoding the “gatekeeper” of mitochondrial Ca2+ uniporter complex (mtCU), will be used to induce mitochondrial Ca2+ overload. In the same manner, deletion of Emre, the gene encoding the essential regulator of the mtCU, will be used to eliminate mtCU activity and lower mitochondrial Ca2+. The overall objective in this application is to systematically compare the effects of increased and decreased mitochondrial Ca2+ on measures of cardiac health – mitochondrial function, tissue histology, contractility before and after stimulation – in homeostasis and in two different types of induced heart failure. The central hypothesis is that elevated mtCa2+ impairs heart function in homeostasis and in HFrEF, whereas lowered mtCa2+ has negative effects in energetically demanding states and in HFpEF. The rationale is that based on the literature and our preliminary data, pressure overload forces the heart to work harder, elevating mitochondrial Ca2+, while some indications suggest that mice fed the high fat/high sucrose diet with L-NAME have lower mitochondrial Ca2+. Hence, in the former conditions, increased mitochondrial Ca2+ is detrimental, and in the latter, decreased mitochondrial Ca2+ is detrimental. The central hypothesis will be tested by pursuing two specific aims: 1) Assess how elevated and reduced mitochondrial Ca2+ impact cardiac homeostasis; and 2) Assess how elevated and reduced mitochondrial Ca2+ impact HFrEF and HFpEF- MetS. This research is conceptually innovative in using genetic manipulation to modulate mitochondrial Ca2+, and in directly comparing elevated and reduced mitochondrial Ca2+ in models approximating HFrEF and HFpEF. The outcomes of this research are expected to be significant by establishing a new paradigm regarding mitochondrial Ca2+ in HFrEF and HFpEF, with the potential to inform future therapeutic strategies.

项目概要/摘要心力衰竭是全球死亡的主要原因，通常与能量生产不足有关线粒体对细胞质 Ca2+ 的吸收在能量产生与能量匹配方面发挥着关键作用。 A 刺激 TP 产生的需求然而，线粒体 Ca2+ 过量会导致渗透性。转变孔开放和潜在的细胞死亡的心力衰竭动物模型更类似于心脏。在一些研究中，射血分数降低 (HFrEF) 衰竭与线粒体 Ca2+ 增加有关其他人线粒体 Ca2+ 减少；关于线粒体 Ca2+ 在心脏中的作用，我们知之甚少；射血分数保留的衰竭（HFpEF）的长期目标是帮助开发限制射血分数的治疗方法。或在适当时恢复线粒体 Ca2+ 以改善 HFrEF 和 HFpEF 的临床结果，这应用程序将绘制线粒体 Ca2+ 增加和减少对心脏功能障碍的影响在体内平衡以及压力超载和高脂肪/高蔗糖饮食的 L-NAME 小鼠模型中。他莫昔芬诱导的 Micu1 心脏特异性缺失，Micu1 是编码线粒体“看门人”的基因 Ca2+ 单向转运蛋白复合物 (mtCU) 将用于以相同的方式诱导线粒体 Ca2+ 过载。删除 Emre（编码 mtCU 必需调节因子的基因）将用于消除 mtCU 活性和降低线粒体 Ca2+ 本应用的总体目标是系统地比较线粒体 Ca2+ 增加和减少对心脏健康指标的影响 – 线粒体功能，组织组织学、刺激前后的收缩性——稳态和两种不同类型的诱导中心假设是 mtCa2+ 升高会损害体内平衡和心脏功能。 HFrEF，而降低的 mtCa2+ 在能量要求较高的状态和 HFpEF 中具有负面影响。基本原理是，根据文献和我们的初步数据，压力超负荷迫使心脏工作更难，提高线粒体 Ca2+，而一些迹象表明小鼠喂食高脂肪/高蔗糖含有 L-NAME 的饮食具有较低的线粒体 Ca2+，因此，在以前的条件下，线粒体 Ca2+ 增加。 Ca2+ 是不健康的，而在后者中，线粒体 Ca2+ 减少是不健康的。通过追求两个具体目标进行测试：1) 评估如何升高和降低线粒体 Ca2+ 影响心脏稳态；以及 2) 评估线粒体 Ca2+ 升高和降低如何影响 HFrEF 和 HFpEF- 这项研究在概念上是创新的，利用基因操作来调节线粒体 Ca2+，并在接近 HFrEF 的模型中直接升高比较并降低线粒体 Ca2+ 和 HFpEF 通过建立新的范式预计将取得重大成果。关于 HFrEF 和 HFpEF 中线粒体 Ca2+ 的研究，有可能为未来的治疗策略提供信息。