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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地刺激ATP的合成，但过量的水平会导致线粒体衰竭和细胞死亡。这种钙超载是一个突出的病理途径，在疾病在多器官系统中。在心脏中，这种现象在心脏病发作期间被注意到，局部缺血导致钙在细胞质中积累，随后使线粒体过载。心脏失败，线粒体也更容易受到钙超载。钙进入线粒体通过称为线粒体钙单向转运体的多亚基钙激活通道。在动物模型中，单向转运蛋白的遗传抑制在急性疾病中表现出保护作用。在慢性病中，虽然抑制钙超载是保护性的，但也可能存在轻度钙超载的基础要求。线粒体钙摄取然而，目前还没有具体的治疗方法来预防钙超负荷或其下游影响。体内单向转运体的药理学调节受试剂限制其选择性差、细胞不可渗透或产生脱靶效应。一个关键的差距，调节单向转运蛋白是我们对孔形成亚基MCU如何调节的有限理解。最近的结构研究揭示了单向转运蛋白复合体的结构和机制对于钙选择性和门控，为进一步的通道结构-功能研究奠定了基础。调控在这个建议中，主要研究者运用他们在结构生物学方面的互补技能和线粒体功能测定来确定这种作用的药理学和基于蛋白质的机制。渠道监管首先，使用计算、电生理和结构的组合，方法，我们将研究单向转运蛋白抑制剂，是细胞渗透性和特异性，并用于急性或慢性损伤。第二，利用新的分子工具，诱变和结构生物学，我们将确定单向转运蛋白亚基MCUB如何通过单向转运蛋白抑制钙摄取。采取总之，我们的研究将揭示单向转运蛋白调节的新形式，这些形式可能被开发成治疗心血管和其他疾病。