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: 8479095
• 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/8479095
• 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; Esthetics; 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）：最近，基于啮齿动物和非人灵长类动物中越来越多的临床前证据，临床上常用的麻醉剂对发育中的大脑具有神经毒性，并可能导致长期的神经行为异常，对婴儿和儿童的麻醉安全性产生了很大的担忧。因此，麻醉剂神经毒性的临床相关性以及用于早期检测麻醉剂诱导的神经元损伤的生物标志物的开发是公共卫生的紧迫问题。由于多种神经元脂质在神经系统中起着特定的作用，脑内的微小扰动可导致脑、脑脊液（CSF）中脂质的变化， 和血浆。全身麻醉药由于其脂溶性，容易进入大脑，溶解到细胞膜中，穿透细胞器，干扰神经元脂质组的动力学，并对发育中的神经系统产生深远影响（神经毒性）。我们假设，在麻醉剂诱导的脑损伤的非常早期阶段，麻醉剂对脑脂质的干扰在患者的脑组织、CSF和/或血浆中是明显的，并且这些改变的脂质可以作为用于早期检测麻醉剂神经毒性的生物标志物。我们相信，麻醉剂暴露引起的脂质变化可以在脑损伤的早期阶段通过我们的使能技术，鸟枪脂质组学检测到，我们最近在NIH资金的支持下开创了这项技术。这项技术的力量已经在发现CSF和血浆中的脂质改变伴随着阿尔茨海默病脑组织的变化中得到了证明。在申请中，我们将利用现有的研究项目，其中我们在FDA的合作者正在对发育中的猴模型中的麻醉诱导的神经元损伤进行研究，该研究已被证明对于告知人类药理学，生理学，毒理学，我们的假设得到了初步研究的有力支持，初步研究表明，脑，CSF，和血浆中的药物。为了进一步验证我们的假设，我们将（1）确定猴脑组织中脂质含量的变化发生在更早的阶段（即，与从增强的神经元细胞死亡和/或基因表达变化所揭示的相比，麻醉剂暴露的持续时间更短;（2）确定暴露于麻醉剂的猴的CSF和血浆中的脂质改变发生在与脑组织中脂质含量和/或组成变化检测到的阶段平行的阶段;和（3）验证 暴露于麻醉剂的猴的CSF和血浆中表现出的改变的脂质可作为早期检测麻醉剂诱导的神经毒性的生物标志物。拟议的研究为发现一组特异性和敏感的脂质生物标志物以在CSF和/或血浆中的早期阶段检测麻醉剂神经毒性提供了巨大的希望，这些生物标志物可用于未来的转化研究。这项研究也可能提供深入了解生化机制的全身麻醉神经毒性。