权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mitochondrial Effects on Sensitivity to Anesthetics

线粒体对麻醉药敏感性的影响

基本信息

批准号：
7930317
负责人：
Margaret Mary Sedensky
金额：
$ 17.14万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7930317
关键词：
Affect Anabolism Anesthesia procedures Anesthetics Animal Behavior Animal Model Animals Behavior Behavior Control Binding Binding Sites Caenorhabditis elegans Cells Child Clinical Complex Data Defect Diagnosis Electron Transport Electrons Functional disorder Funding Gases Gene Expression Genes Homologous Gene Human Kinetics Laboratories Location Mammals Measures Mediating Metabolic Metabolism Microarray Analysis Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Complex I Mitochondrial Proteins Modeling Molecular Molecular Profiling Molecular Target Movement Mutation NADH dehydrogenase (ubiquinone)Nematoda Neurons Oxidative Phosphorylation Pathway interactions Patients Physiological Point Mutation Proteins RNA Interference Research Personnel Respiratory physiology Role Sorting - Cell Movement Sum Testing Translations Ubiquinone Work base behavior change gene discovery mutant novel protein complex response sevoflurane

项目摘要

Our laboratory exploits a very simple animal model, the nematode C. elegans, to investigate the molecular mechanism of volatile anesthetic action. We have established that genes and physiologic pathways that alter anesthetic sensitivity in the nematode also alter sensitivity in mammals. The importance of the fact that the same molecular pathways affect sensitivity across different species is hard to overstate. We have identified a group of genes that alter mitochondrial function and control the sensitivity of C. elegans to volatile anesthetics (VAs). A point mutation in gas-1, which encodes the 49 kDa subunit of complex I of the mitochondrial electron transport chain, causes the animal to be very hypersensitive to all VAs. In addition, we have found that a subset of patients, children with metabolic defects most clearly related to complex I function, are profoundly hypersensitive to sevoflurane. This finding provides a clinical correlate to the basic study of very simple animal model. The sum of our work clearly implicates mitochondrial function as a novel mechanism that contributes to the control of anesthetic response. In this proposal we will extend our studies in the nematode to test our hypothesis that alterations in complex I function change anesthetic sensitivity via direct effects on metabolism, and via indirect effects on specific downstream proteins. The specific aims to test these hypotheses are: 1. Determine which subunits of complex I alter anesthetic sensitivity in C. elegans. The function of this complex is key to mediating behavior in VAs in nematodes, and may have a parallel role in patients with mitochondrial disease. 2. Measure the effect of volatile anesthetics on ubiquinone binding to complex I. We hypothesize that this binding site may be a target of action for volatile anesthetics. 3. Determine genes and gene sets whose expression changes as a downstream effect of complex I dysfunction. We will carefully focus our analysis to expression profiles that alter anesthetic sensitivity by a subtraction strategy that focuses on changes specific to neurons. The microarray analysis will be validated by using RNAi to specifically reduce levels of expression of genes discovered in thisaim, and test the resultant effects on behavior in VAs This superb animal model allows putative molecular targets of VAs to be confirmed or refuted by assessing whole animal behavior. Such a tractable animal model is crucial to unraveling the mechanism of action of this very important class of anesthetic agents.

我们的实验室利用一个非常简单的动物模型，线虫线虫，来研究分子挥发性麻醉剂的作用机制。我们已经确定了基因和生理途径改变线虫的麻醉敏感度也会改变哺乳动物的敏感度。这个事实的重要性相同的分子途径影响不同物种的敏感性，这一点怎么强调都不为过。我们有确定了一组改变线粒体功能和控制线虫对挥发性物质敏感性的基因麻醉药(VAS)。GAS-1中的一个点突变，它编码的是该病毒复合体I的49 kDa亚基线粒体电子传输链，导致动物对所有VAS非常敏感。此外, 我们已经发现，有代谢缺陷的儿童患者的一部分最明显地与复合体I有关功能，对七氟醚极度敏感。这一发现为临床提供了与基本的研究非常简单的动物模型。我们的工作总结清楚地表明线粒体的功能是一种新的有助于控制麻醉反应的机制。在这项建议中，我们将延长我们的研究在线虫中测试我们的假设，即复合体I功能的变化通过对新陈代谢的直接影响，以及对特定下游蛋白质的间接影响。具体目的是检验这些假设是：1.确定复合体的哪些亚基改变了C。优雅女装。这个复合体的功能是调节线虫VAS行为的关键，并可能具有在线粒体疾病患者中的平行作用。2.测量挥发性麻醉药对患者的影响泛醌与络合物的结合。我们推测这个结合部位可能是挥发性物质的作用靶点。麻醉剂。3.确定其表达变化作为下游效应的基因和基因集复杂性I型功能障碍。我们将仔细分析改变麻醉剂的表达模式通过专注于神经元特有变化的减法策略提高敏感度。基因芯片分析将通过使用RNAi来具体降低在这一目标中发现的基因的表达水平来进行验证，并在VAS中测试结果对行为的影响这种极好的动物模型允许假定的分子靶标通过评估整个动物的行为来证实或驳斥VAS的观点。这样一个容易驯服的动物模型是对于解开这类非常重要的麻醉剂的作用机制至关重要。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I.

DOI：
10.1371/journal.pone.0042904
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Quintana A;Morgan PG;Kruse SE;Palmiter RD;Sedensky MM
通讯作者：
Sedensky MM

Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans.

DOI：
10.1371/journal.pone.0006607
发表时间：
2009-08-12
期刊：
PloS one
影响因子：
3.7
作者：
Falk MJ;Rosenjack JR;Polyak E;Suthammarak W;Chen Z;Morgan PG;Sedensky MM
通讯作者：
Sedensky MM

Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans.

DOI：
10.1016/j.mito.2014.12.004
发表时间：
2015-01
期刊：
MITOCHONDRION
影响因子：
4.4
作者：
Morgan, P. G.;Higdon, R.;Kolker, N.;Bauman, A. T.;Ilkayeva, O.;Newgard, C. B.;Kolker, E.;Steele, L. M.;Sedensky, M. M.
通讯作者：
Sedensky, M. M.

Altered redox status of coenzyme Q9 reflects mitochondrial electron transport chain deficiencies in Caenorhabditis elegans.

辅酶 Q9 氧化还原状态的改变反映了秀丽隐杆线虫线粒体电子传递链的缺陷。