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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.

我们的实验室利用了一个非常简单的动物模型，线虫C。elegans，to investigate调查the molecular分子挥发性麻醉剂的作用机制。我们已经确定，基因和生理途径，改变线虫对麻醉剂的敏感性也会改变哺乳动物的敏感性。重要的是，相同的分子途径影响不同物种的敏感性，这一点很难夸大。我们有确定了一组改变线粒体功能和控制C. elegans到volatile 麻醉剂（VA）。Gas-1中的一个点突变，其编码Gas蛋白复合物I的49 kDa亚基，线粒体电子传递链，导致动物对所有VA非常过敏。此外，本发明还提供了一种方法，我们已经发现，一部分患有代谢缺陷的儿童患者，功能，对七氟烷高度过敏。这一发现提供了一个临床相关的基本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功能是一种新的有助于控制麻醉反应的机制。在这个建议中，我们将扩大我们的研究，我们的假设是，复合物I功能的改变会通过直接影响代谢，并通过对特定下游蛋白质的间接影响。具体目标是检验这些假设是：1。确定复合物I的哪些亚基改变C. 优美的该复合物的功能是介导线虫VA行为的关键，并且可能具有与VAs相似的功能。在线粒体疾病患者中发挥平行作用。2.测量挥发性麻醉剂对泛醌与复合物I结合。我们推测，这个结合位点可能是挥发性的作用靶点。麻醉剂3.确定其表达变化作为下游效应的基因和基因集。复合体I功能障碍我们将仔细地集中我们的分析，以表达谱，改变麻醉通过减法策略，专注于神经元特异性的变化。微阵列分析将通过使用RNAi来特异性地降低在此目的中发现的基因的表达水平来验证，并测试其对VA行为的影响这个极好的动物模型允许假定的分子靶点通过评估整个动物行为来证实或反驳VA。这样一个易于处理的动物模型，这对阐明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。