Regulation of the mitochondrial calcium uniporter

线粒体钙单向转运蛋白的调节

基本信息

批准号：
10539759
负责人：
Dipayan Chaudhuri
金额：
$ 56.41万
依托单位：
UNIVERSITY OF UTAH
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：
2022-07-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539759
关键词：
ATP Synthesis Pathway Acute Acute Disease Affect Affinity Animal Model Architecture Binding Biological Assay Biology Calcium Cardiovascular Diseases Cardiovascular system Cell Death Cells Charge Chemicals Chronic Chronic Disease Clinical Pharmacology Complex Cryoelectron Microscopy Cytoplasm Dimerization Disease Drug Design Electrophysiology (science)Failure Functional disorder Genetic Goals Group Structure Heart Heart Injuries Heart failure Homeostasis Human Impairment Injury Investigation Ischemia Location Mediating Mitochondria Mitochondrial Matrix Molecular Mutagenesis Myocardial Infarction N-terminal Pathologic Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Physiological Positioning Attribute Principal Investigator Proteins Publications Regulation Signal Transduction Structure Swelling Testing Vertebral column Work base body system calcium uniporter clinical translation improved in vivo inhibitor innovation lipophilicity multimodality new therapeutic target novel preservation prevent research study skills small molecule stoichiometry structural biology targeted treatment tool uptake voltage

项目摘要

PROJECT SUMMARY Calcium influx into the mitochondria can potently stimulate ATP synthesis, but excessive levels cause mitochondrial failure and cell death. Such calcium overload is a prominent pathological pathway in disease in multiple organ systems. In the heart, this phenomenon is noted during heart attacks, when prolonged ischemia causes calcium to accumulate in the cytoplasm and subsequently overload mitochondria. In heart failure, mitochondrial are also more susceptible to calcium overload. Calcium enters the mitochondria through a multi-subunit calcium-activated channel known as the mitochondrial calcium uniporter. In animal models, genetic inhibition of the uniporter has appeared protective in acute disease. In chronic diseases, though inhibition of calcium overload is protective, there may also be basal requirements for milder mitochondrial calcium uptake. Currently, however, there are no specific therapies to prevent calcium overload or its downstream affects. Pharmacological modulation of the uniporter in vivo is limited by agents that are poorly selective, cell impermeable, or produce off-target effects. A critical gap in the ability to better modulate the uniporter is our limited understanding of how the pore-forming subunit, MCU, is regulated. Recent elegant structural studies have revealed the architecture of the uniporter complex, and mechanisms for calcium selectivity and gating, setting the stage for structure-function investigations of further channel regulation. In this proposal, the principal investigators apply their complementary skills in structural biology and mitochondrial functional assays to define pharmacological and protein-based mechanisms for such channel regulation. First, using a combination of computational, electrophysiological, and structural approaches, we will investigate uniporter inhibitors that are cell-permeable and specific, and useful for either acute or chronic injury. Second, using new molecular tools, mutagenesis, and structural biology, we will identify how the uniporter subunit MCUB leads to inhibition of calcium uptake through the uniporter. Taken together, our studies will reveal novel forms of uniporter regulation that may be developed into therapies for cardiovascular and other disorders.

项目摘要钙流入线粒体可以有效刺激ATP合成，但过多的水平会导致线粒体衰竭和细胞死亡。这种钙超负荷是疾病中突出的病理途径在多器官系统中。在心脏病中，心脏病发作时会注意到这种现象，延长了缺血会导致钙积聚在细胞质中，随后过载线粒体。内心故障，线粒体也更容易受到钙超负荷的影响。钙进入线粒体通过称为线粒体钙Uniporter的多支亚基钙激活通道。在动物中模型，遗传抑制单位者在急性疾病中似乎具有保护性。在慢性疾病中，尽管抑制钙超负荷是保护性的，但也可能有较轻的基础要求线粒体钙摄取。但是，目前尚无预防钙的特定疗法超负荷或其下游影响。体内单位物质的药理调节受代理的限制选择性不佳，细胞不渗透或产生脱靶效应。更好的能力的关键差距调节Uniporter是我们对如何调节孔成孔亚基MCU的有限理解。最近的优雅结构研究揭示了Uniporter综合体的结构和机制对于钙的选择性和门控，为进一步通道的结构功能研究设定了阶段规定。在该提案中，首席研究人员将其互补技能应用于结构生物学以及线粒体功能测定法，以定义此类药理和蛋白质的机制通道调节。首先，结合了计算，电生理和结构方法，我们将研究细胞可渗透且特异性的Uniporter抑制剂，并且对任何一种急性或慢性损伤。第二，使用新的分子工具，诱变和结构生物学，我们将确定Uniporter亚基MCUB如何导致通过Uniporter抑制钙的摄取。拍摄总之，我们的研究将揭示可能发展为疗法的新型Uniporter调节形式心血管和其他疾病。