Anesthetic-Induced Neurotoxicity: Molecular Pathways and Genetic Risk Factors

麻醉引起的神经毒性：分子途径和遗传风险因素

基本信息

批准号：
10549751
负责人：
DAVID WASSARMAN
金额：
$ 34.99万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549751
关键词：
Acceleration Acute Affect Age Aging Alleles American Anesthesia procedures Anesthetics Animal Model Animals Awareness Behavioral Biological Caring Child Clinical Research Clinical Trials Cognitive Collection Communities Data Delirium Diagnostic Drosophila genus Drosophila melanogaster Elderly Electron Transport Environmental Risk Factor Exposure to Foundations Functional disorder Gene Expression General Population General anesthetic drugs Generations Genes Genetic Genetic Markers Genetic Polymorphism Genetic Predisposition to Disease Genetic Screening Goals Heritability Heterozygote High Prevalence Hour Human Hyperoxia Hypersensitivity Impaired cognition Individual Isoflurane Leigh Disease Measures Mediating Medicine Metabolic Metabolic Pathway Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Complex I Modeling Molecular Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Neuroglia Neurons Nuclear Nucleotides Operative Surgical Procedures Orthologous Gene Outcome Study Oxygen Pathway interactions Patients Penetrance Perioperative Persons Pharmacogenomics Phenotype Play Population Predisposition Pregnant Women Prevention Preventive Public Health Quantitative Reverse Transcriptase PCR Reporting Research Risk Risk Assessment Risk Factors Role Shapes Societies System Testing Therapeutic Therapeutic Intervention Toxic effect Volatilization aged aging brain brain health clinically relevant disease-causing mutation experience fly genetic approach genetic manipulation genetic risk factor genome wide association study high throughput screening middle age mitochondrial dysfunction model organism mortality mutant neurotoxicity personalized medicine pre-clinical prophylactic response sevoflurane transcriptome sequencing

项目摘要

Some individuals undergoing anesthesia and surgery will experience anesthetic-induced neurotoxicity (AiN) attributable to volatile general anesthetic agents (VGAs). AiN after exposure to VGAs can present with different phenotypes, including acute neurodegeneration, delirium, lifelong cognitive impairment in children and accelerated or even de novo neurodegeneration in the aged. Despite controversial clinical trials, the FDA, in a far-reaching response to recent data, has issued a warning on the use of VGAs in pregnant women and young children. Furthermore, the American Society of Anesthesiologists' Perioperative Brain Health Initiative has raised awareness of AiN for the aged brain. As neither the pathophysiology of AiN nor its risk factors are understood, there are neither prophylactic nor therapeutic measures. Our underlying hypothesis is that heritable factors determine the threshold for AiN vulnerability while biological and environmental variables shape its phenotype. We propose to approach AiN with a pharmacogenomic strategy in the fruit fly Drosophila melanogaster. We will use the ND2360114 strain, which is a model of Leigh syndrome (a human neurodegenerative disease caused by mutation of NDUFS8, the mammalian ortholog of ND23). Exposure of ND2360114 flies to VGAs results in four striking phenotypes: (1) young flies are equally hypersensitive to the behavioral effects of isoflurane and sevoflurane (reproducing the human phenotype), (2) middle-aged flies incur significant mortality within 24 hours after waking up from isoflurane, (3) genetic and environmental manipulations profoundly modulate mortality, and (4) phenotypically normal ND2360114/+ flies become sensitized to AiN from isoflurane at an advanced age thereby. We will use ND2360114 flies as a sensitized model of AiN with rapid, unambiguous readout. To investigate the modulatory role of genetic background on AiN, we will use genome-wide association study (GWAS) analysis to identify nucleotide polymorphisms that modify AiN in ND2360114/+ flies. To determine the scope of heterozygous mutations that increase the risk of AiN, we will screen candidate mutants in mitochondrial metabolic pathways. To identify key metabolic regulators of AiN, we will use RNA-seq under experimental conditions that result in different mortality rates. These studies are significant because exposure to VGA affects millions of people of all ages every year and concerns of AiN are widespread. Complications from exposure to anesthesia and surgery have long-lasting consequences. Considering genetic background when assessing the individual risk of AiN is a step towards personalized medicine. Understanding its pathophysiology offers a path to informed prevention and treatment.

一些接受麻醉和手术的人会经历麻醉诱导的神经毒性（AIN）归因于挥发性全身麻醉剂（VGAS）。暴露于VGA后的AIN可能会出现不同的表型，包括急性神经变性，del妄，儿童终身认知障碍老年人加速甚至从头神经变性。尽管有争议的临床试验，但FDA在对最近数据的深远回应，已发出警告，警告孕妇和年幼的孩子。此外，美国麻醉师学会的围手术期脑健康计划已经提高了对老年大脑AIN的认识。因为AIN的病理生理学或其危险因素都不是理解，既没有预防性也没有治疗措施。我们的基本假设是，可遗传的因素决定了AIN脆弱性的阈值，而生物学环境变量塑造了其表型。我们建议用药物基因组学接近AIN 果蝇果蝇的策略。我们将使用ND2360114菌株，这是Leigh的模型综合征（由NDUFS8突变引起的人类神经退行性疾病，是哺乳动物的直系同源 ND23）。 ND2360114苍蝇暴露于VGAS会导致四种引人注目的表型：（1）年轻的苍蝇同样是对异氟烷和七氟醚（重现人类表型）的行为影响过敏，（2）从异氟烷醒来后的24小时内，中年苍蝇在（3）遗传和环境操纵深刻调节死亡率，（4）表型正常ND2360114/+苍蝇因此，从异氟烷中对AIN敏感。我们将使用ND2360114苍蝇作为 AIN的敏化模型，具有快速，明确的读数。研究遗传的调节作用 AIN背景，我们将使用全基因组关联研究（GWAS）分析来识别核苷酸多态性在ND2360114/+ FLIES中修改AIN。确定杂合突变的范围增加AIN的风险，我们将在线粒体代谢途径中筛选候选突变体。识别 AIN的主要代谢调节剂，我们将在实验条件下使用RNA-SEQ，导致不同死亡率。这些研究很重要，因为接触VGA会影响每年数百万年龄段的人 AIN的担忧是广泛的。接触到麻醉和手术的并发症具有长期的结果。评估AIN的个人风险时考虑遗传背景是迈向的一步个性化医学。了解其病理生理学为预防和治疗提供了知情的途径。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Serial Anesthesia Array for the High-Throughput Investigation of Volatile Agents Using Drosophila melanogaster.

DOI：
10.3791/65144
发表时间：
2023-02-24
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Olufs ZPG;Johnson-Schlitz D;Wassarman DA;Perouansky M
通讯作者：
Perouansky M

Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (Drosophila melanogaster) to Ether and Non-Ether Volatile Anesthetics.

DOI：
10.3390/ijms24031843
发表时间：
2023-01-17
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Borchardt, Luke A. A.;Scharenbrock, Amanda R. R.;Olufs, Zachariah P. G.;Wassarman, David A. A.;Perouansky, Misha
通讯作者：
Perouansky, Misha

A Crack at MAC.