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Rapamycin as a potential treatment for succinate dehydrogenase deficiency

雷帕霉素作为琥珀酸脱氢酶缺乏症的潜在治疗方法

基本信息

批准号：
10291638
负责人：
Eugenia Villa Cuesta
金额：
$ 35.24万
依托单位：
ADELPHI UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291638
关键词：
Address Aging Amino Acids Animals Area Biological Assay Cancer Patient Cancerous Carbon Catabolism Cells Characteristics Chemopreventive Agent Complement DNA Data Development Diet Disease Drosophila genus Drosophila melanogaster Environment Enzymes Evolution FDA approved FRAP1 gene Genes Genetic Models Genotype Glioblastoma Glutamate Dehydrogenase Glutamates Glutamine Goals Grant Growth Health Impairment In Vitro Laboratories Lead Longevity Malignant Neoplasms Mediating Metabolic Metabolism Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Genetics Mutation Nitrogen Nuclear Organism Oxygen Consumption Pathology Pathway interactions Pharmaceutical Preparations Physiological Physiology Play Proteins Research Resistance Role Sampling Sirolimus Starvation Students Succinate Dehydrogenase Supplementation Testing United States National Institutes of Health alpha ketoglutarate base cancer therapy environmental intervention experimental study feeding fly gene therapy genetic analysis improved in vivo inhibitor/antagonist member metabolic abnormality assessment metabolic rate metabolomics mitochondrial dysfunction mitochondrial genome mitochondrial metabolism mutant novel novel therapeutics response tool tumor undergraduate student

项目摘要

Rapamycin is an inhibitor of the mechanistic Target of Rapamycin pathway (mTOR). This drug has anti-carcinogenic and pro-longevity characteristics. We, and others, have shown that rapamycin could also be considered as a treatment for mitochondrial disorders since feeding rapamycin to genetic models for mitochondrial disorders improve the pathology associated with the diseases. However, resistance to rapamycin hinders the efficacy of such treatment. Molecular genetic analysis in D. melanogaster provides unique approaches to uncover the basic mechanism of insensitivity of rapamycin. In this context, we have discovered that introgressed strains of Drosophila harboring mitochondrial DNA form D. simulans in a D. melanogaster nuclear DNA do not respond to rapamycin treatment while wild type D. melanogaster or wild type D. simulans respond to the drug. In addition, we discovered that rapamycin beneficial effect on mitochondrial function requires a shift of metabolism, in particular, the catabolism of proteins. Wild type D. melanogaster fed a diet rich on proteins, or lacking proteins do not respond to the increase on metabolic rate mediated by rapamycin. Metabolomics analysis and preliminary molecular genetics analysis with mutants for the glutamate dehydrogenase, the enzyme that catabolize glutamate into alpha-ketoglutarate, have identified the critical role of the glutamine, glutamate and alpha-ketoglutarate anapleourotic (Gln-Glu-αKG) pathway in the response to rapamycin. Based on our observations and the documented effects of the sensitivity and the resistance to rapamycin, in this proposal we will test the hypothesis that rapamycin sensitivity depends upon the qualitative used of the Gln-Glu-αKG pathway by the cell. To test this hypothesis, we will use a combination of introgressed mitochondrial DNAs strains, with and without mutations on genes that codify for several members of the the Gln-Glu-αKG pathway. We will study the sensitivity and resistance to rapamycin treatment by exposing the aforementioned strains to rapamycin treatment in the presence and absence of amino acids supplementation. We will complement those analyses with metabolomics assays that will depict the metabolic space of the resistance to rapamycin. Overall, this proposal aims to identified the hallmarks of the insensitivity to rapamycin treatment using a unique set of tools provided with the use of mitochondria introgressed strains.

雷帕霉素是雷帕霉素途径的机制靶点(MTOR)的抑制剂。这种药具有抗癌、延年益寿的特点。我们和其他人已经证明了雷帕霉素也可以被认为是治疗进食后线粒体疾病的一种方法。雷帕霉素对线粒体疾病遗传模型的改善与病理相关这些疾病。然而，对雷帕霉素的耐药性阻碍了这种治疗的效果。黑腹盘藻的分子遗传分析提供了独特的方法来揭示雷帕霉素不敏感的机制。在此背景下，我们发现，引入含有线粒体DNA的果蝇品系在黑腹果蝇体内形成拟态果蝇核DNA对雷帕霉素处理没有反应，而野生型黑腹葡萄球菌或野生型 D型模拟器对药物有反应。此外，我们发现雷帕霉素有有益的作用对线粒体功能的影响需要新陈代谢的改变，特别是蛋白质的分解代谢。野生型D.黑腹鼠摄食富含蛋白质的食物或缺乏蛋白质的食物对雷帕霉素介导的代谢率增加。代谢组学分析及初步研究谷氨酸脱氢酶突变体的分子遗传学分析将谷氨酸分解成α-酮戊二酸，确定了谷氨酰胺的关键作用，谷氨酸和α-酮戊二酸脱氢酶(Gln-Glu-αKG)途径在细胞免疫应答中的作用雷帕霉素。根据我们的观察和记录的敏感性和对雷帕霉素的耐药性，在这项建议中，我们将检验雷帕霉素敏感性的假设依赖于细胞对谷氨酰胺-谷氨酸-αKG通路的定性利用。为了测试这一点假设，我们将使用导入的线粒体DNA菌株与和的组合在编码Gln-Glu-αKG途径几个成员的基因上没有突变。我们将通过暴露对雷帕霉素治疗的敏感性和耐药性来研究上述菌株对雷帕霉素在氨基酸存在和不存在时的处理补充。我们将用代谢组学分析补充这些分析，这些分析将描述雷帕霉素耐药的代谢空间。总体而言，这项建议旨在确定使用随附的一套独特工具对雷帕霉素治疗不敏感的特征线粒体的使用导入了菌株。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sirt4 Modulates Oxidative Metabolism and Sensitivity to Rapamycin Through Species-Dependent Phenotypes in Drosophila mtDNA Haplotypes.

Sirt4 通过果蝇 mtDNA 单倍型的物种依赖性表型调节氧化代谢和对雷帕霉素的敏感性。

DOI：
10.1534/g3.120.401174
发表时间：
2020
期刊：
G3 (Bethesda, Md.)
影响因子：
0
作者：
Sejour,Richard;Sanguino,RogerA;Mikolajczak,Monika;Ahmadi,Walishah;Villa-Cuesta,Eugenia
通讯作者：
Villa-Cuesta,Eugenia

Preparation of Mitochondrial Enriched Fractions for Metabolic Analysis in Drosophila.