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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.

项目总结/摘要心力衰竭是全球死亡的主要原因，通常与心脏能量产生不足有关。线粒体线粒体对胞质Ca 2+的摄取在使能量产生与细胞内Ca 2+浓度相匹配方面起着关键作用。刺激ATP的生产。然而，线粒体Ca 2+过量可导致通透性增加，过渡孔开放和潜在的细胞死亡。心力衰竭的动物模型更接近心脏在一些研究中，射血分数降低的衰竭（HFrEF）与线粒体Ca 2+增加有关，在其他人中线粒体Ca 2+减少;关于线粒体Ca 2+在心脏中的作用知之甚少射血分数保留（HFpEF）。长期目标是帮助开发治疗方法，或在适当时恢复线粒体Ca 2+以改善HFrEF和HFpEF的临床结局，应用程序将绘制出线粒体Ca 2+增加和减少对心脏功能障碍的贡献在稳态和压力超负荷和高脂肪/高糖饮食与L-NAME的小鼠模型中。他莫昔芬诱导的心肌特异性线粒体“看门人”基因Micu 1缺失 Ca 2+单向转运体复合物（mtCU）将用于诱导线粒体Ca 2+过载。以同样的方式，缺失编码mtCU基本调节因子的基因Emre将用于消除mtCU 活性和线粒体Ca ~（2+）降低。本申请的总体目标是系统地比较线粒体Ca 2+增加和减少对心脏健康-线粒体功能测量的影响，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心衰核心假设是线粒体Ca 2+升高会损害体内平衡和心功能， HFrEF，而降低的mtCa 2+在能量需求状态和HFpEF中具有负面影响。的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，升高线粒体Ca 2+，而一些迹象表明，小鼠喂养高脂肪/高糖添加L-NAME的饲料具有较低的线粒体Ca ~（2+）。因此，在前一种情况下， Ca 2+是有害的，在后者中，线粒体Ca 2+减少是有害的。核心假设将通过追求两个具体目标进行测试：1）评估线粒体Ca 2+的升高和降低如何影响心脏稳态; 2）评估线粒体Ca 2+升高和降低如何影响HFrEF和HFpEF- MetS。这项研究在利用遗传操作调节线粒体Ca 2+方面具有概念创新性，以及在接近HFrEF的模型中直接比较线粒体Ca 2+升高和降低， HFpEF。本研究的成果有望通过建立一个新的范式而产生重大意义关于HFrEF和HFpEF中的线粒体Ca 2+，有可能为未来的治疗策略提供信息。