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

• 批准号: 10337060
• 负责人: Michael Perouansky
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10337060
• 关键词: 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; 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 structure; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nucleotides; Operative Surgical Procedures; Orthologous Gene; Outcome Study; Oxygen; Pathway interactions; Patients; Penetrance; Perioperative; Persons; Pharmacogenomics; Phenotype; Play; Population; 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; aged; aging brain; base; 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; mortality; mutant; neurotoxicity; personalized medicine; pre-clinical; prophylactic; response; sevoflurane; transcriptome sequencing

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个体会经历麻醉诱导的神经毒性（AIN） 可归因于挥发性全身麻醉剂（VGA）。暴露于VGA后的AIN可以呈现不同的 表型，包括急性神经变性、谵妄、儿童终身认知障碍和 老年人的神经退行性变加速甚至从头发生。尽管有争议的临床试验，FDA，在 对最近的数据做出了深远的回应，对孕妇使用VGA发出了警告， 年幼的孩子。此外，美国麻醉医师协会的围手术期脑健康倡议， 提高了老年人对AIN的认识。由于AIN的病理生理学及其危险因素都不是 据了解，既没有预防措施，也没有治疗措施。 我们的基本假设是，遗传因素决定了AIN脆弱性的阈值，而生物学因素决定了AIN脆弱性的阈值。 环境变量塑造了它的表型。我们建议用药物基因组学方法接近AIN。 果蝇的策略。我们将使用ND 2360114菌株，这是Leigh的模型 综合征（由NDUFS 8突变引起的人类神经退行性疾病，NDUFS 8是哺乳动物的直系同源物， ND 23）。ND 2360114果蝇暴露于VGAs导致四种显著的表型：（1）幼蝇与对照组相比， 对异氟烷和七氟烷的行为效应过敏（再现人类表型），（2） 中年果蝇在异氟烷苏醒后24小时内发生显著死亡，（3）遗传和 环境操作深刻调节死亡率，和（4）表型正常ND 2360114/+苍蝇 从而在高龄时对异氟烷中的AiN变得敏感。我们将使用ND 2360114苍蝇作为 AiN的敏化模型，具有快速，明确的读数。探讨遗传因素对细胞凋亡的调节作用， 在AiN的背景下，我们将使用全基因组关联研究（GWAS）分析来识别核苷酸 在ND 2360114/+果蝇中修饰AiN的多态性。为了确定杂合突变的范围， 增加AIN的风险，我们将筛选线粒体代谢途径的候选突变体。以识别 AiN的关键代谢调节因子，我们将在实验条件下使用RNA-seq， 死亡率。 这些研究意义重大，因为暴露于VGA每年影响数百万所有年龄段的人， 对AI的担忧非常普遍。暴露于麻醉和手术的并发症具有长期的 后果在评估AIN的个体风险时考虑遗传背景是迈向 个性化医疗了解其病理生理学提供了一条知情的预防和治疗的途径。