Identification of altered lipids predictive of anesthetic-induced brain injury

鉴定可预测麻醉引起的脑损伤的脂质改变

• 批准号: 8667489
• 负责人: Xianlin Han
• 金额: $ 41.44万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667489
• 关键词: Adverse effects; Alzheimer' s Disease; Anesthesia procedures; Anesthetics; Animal Model; Biochemical; Biological; Biological Markers; Biological Models; Brain; Brain Injuries; Brain region; Cellular Membrane; Cerebrospinal Fluid; Child; Childhood; Clinic; Clinical; Detection; Development; Early Diagnosis; Funding; Future; Gene Expression; General anesthetic drugs; Growth; Human; Individual; Infant; Isoflurane; Ketamine; Left; Lipids; Logic; Mammals; Modeling; Monkeys; Nervous System Physiology; Nervous system structure; Neuraxis; Neuronal Injury; Neurons; Organ; Organelles; Pathology; Patients; Perinatal; Pharmacology; Pharmacology and Toxicology; Physiology; Plasma; Play; Population; Primates; Process; Public Health; Relative (related person); Research Project Grants; Rodent; Role; Safety; Shotguns; Specific qualifier value; Staging; Synapses; Technology; Testing; Tissues; Toxicology; United States National Institutes of Health; base; brain tissue; clinically relevant; cost effective; human population study; insight; lipid solubility; myelination; neurobehavioral; neuron loss; neurotoxic; neurotoxicity; nonhuman primate; pre-clinical; public health relevance; sevoflurane; translational study

DESCRIPTION (provided by applicant): A big concern has recently arisen regarding the safety of anesthesia in infants and children based on the profoundly increasing preclinical evidences in rodents and nonhuman primates that the commonly used anesthetics in clinic are neurotoxic to the developing brain and may cause long-term neurobehavioral abnormalities. Hence, the clinical relevance of anesthetic neurotoxicity as well as the development of biomarkers for early detection of anesthetic-induced neuronal injury is an urgent matter of public health. Since the diversified neuronal lipids play specific roles in the nervous system, small disturbance in the brain could result in changes of lipids in the brain, cerebrospinal fluid (CSF), and plasma. General anesthetics, due to their lipid solubility, readily enter the brain, dissolve into cellular membranes, penetrate organelle, disturb dynamics of neuronal lipidome, and leave far-reaching effects on the developing nervous system (neurotoxicity). We hypothesized that perturbation of brain lipids with anesthetics is manifest in brain tissues, CSF, and/or plasma of patients at a very early stage of anesthetic-induced brain injury, and these changed lipids can serve as biomarker(s) for early detection of anesthetic neurotoxicity. We believe the changes of lipids induced with anesthetic exposure can be detected at a very early stage of brain injury by our enabling technology, shotgun lipidomics, which we have recently pioneered with the support of NIH funding. The power of this technology has been demonstrated in discovery of altered lipids in CSF and plasma in accompanying the changes in brain tissues of Alzheimer's disease. In the application, we will take the advantages of an existing research project in which our collaborators at the FDA are conducting studies on the anesthetic- induced neuronal injury in the developing monkey model, which has proved to be invaluable for informing aspects of human pharmacology, physiology, toxicology, etc. Our hypothesis is strongly supported by the preliminary studies showing that numerous lipid classes were significantly changed in brain, CSF, and plasma of monkeys exposed to anesthetics. To further test our hypothesis, we will (1) identify that the changes of lipid content in monkey brain tissues occur at a much earlier stage (i.e., shorter duration) of anesthetic exposure in comparison to that revealed from the enhanced neuronal cell death and/or changes in gene expression; (2) determine that altered lipids in both CSF and plasma of monkeys which are exposed to anesthetic(s) occurs at the stage parallel to that detected with the changes of lipid content and/or composition in brain tissues; and (3) verify that the altered lipids manifest in CSF and plasma of monkeys exposed to anesthetic(s) can be served as biomarkers for early detection of anesthetic-induced neurotoxicity. The proposed studies hold tremendous promise for the discovery of a panel of specific and sensitive lipid biomarkers for detection of anesthetic neurotoxicity at its early stage in CSF and/or plasma, which can be used for future translational studies. This study might also provide insight into the biochemical mechanism underlying general anesthetic neurotoxicity.

描述（由申请人提供）：基于啮齿动物和非人类灵长类动物的临床前证据的临床前证据，临床医学在诊所中常用的麻醉剂在发育中的大脑中具有神经毒性是长期的神经性神经性异常。因此，麻醉神经毒性的临床相关性以及生物标志物的早期检测到麻醉引起的神经元损伤的发展是公共卫生的紧迫问题。由于多样化的神经元脂质在神经系统中起特定的作用，因此大脑中的微小干扰可能导致脑脂质变化，脑脊液（CSF）， 和等离子体。由于其脂质溶解度，一般麻醉药很容易进入大脑，溶于细胞膜，穿透细胞器，干扰神经元脂肪组的动态，并对发育中的神经系统（神经毒性）产生深远的影响。我们假设，在麻醉性诱发的脑损伤的早期阶段，患者的脑组织，CSF和/或血浆中脑脂质的扰动表现出来，这些变化的脂质可以作为麻醉神经毒性的早期检测。我们认为，在NIH资金的支持下，我们最近在脑损伤的早期阶段就可以在脑损伤的早期阶段检测到脂质的变化。在发现CSF和血浆中脂质变化的情况下，该技术的力量在伴随阿尔茨海默氏病的脑组织变化方面发生了变化。在应用程序中，我们将采用现有研究项目的优势，在该项目中，我们的FDA合作者正在对正在发展中的猴子模型中的麻醉诱发的神经元损伤进行研究，事实证明，这是无价的，对于人类药理，生理学，毒理学等方面的信息。我们的假设有很大的变化。暴露于麻醉药的猴子的血浆。为了进一步检验我们的假设，我们将（1）确定猴子脑组织中脂质含量的变化发生在麻醉暴露的早期阶段（即较短的持续时间）与从增强的神经元细胞死亡和/或基因表达的变化所揭示的相比。 （2）确定猴子的CSF和血浆中的脂质改变了暴露于麻醉剂的脂质发生在与脑组织中脂质含量和/或组成的变化相似的阶段发生。 （3）验证 暴露于麻醉（S）的猴子的CSF和血浆中的脂质改变可以用作早期检测麻醉诱导的神经毒性的生物标志物。拟议的研究对发现一组特异性和敏感的脂质生物标志物在CSF和/或血浆中发现了麻醉神经毒性，这具有巨大的希望，可用于检测麻醉神经毒性。这项研究还可能提供有关全身麻醉神经毒性基础的生化机制的见解。