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）：基于啮齿类动物和非人类灵长类动物临床前证据的不断增加，临床上常用的麻醉剂对发育中的大脑具有神经毒性，并可能导致婴儿和儿童麻醉的安全性，最近引起了人们对婴儿和儿童麻醉安全性的极大关注。长期神经行为异常。因此，麻醉神经毒性的临床相关性以及开发用于早期检测麻醉引起的神经元损伤的生物标志物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发挥着特定的作用，大脑中的微小干扰可能会导致大脑、脑脊液（CSF）、 和血浆。全身麻醉剂由于其脂溶性，很容易进入大脑，溶解到细胞膜中，渗透细胞器，扰乱神经元脂质组的动态，并对发育中的神经系统产生深远的影响（神经毒性）。我们假设麻醉药对脑脂质的扰动在麻醉引起的脑损伤的早期阶段就表现在患者的脑组织、脑脊液和/或血浆中，这些改变的脂质可以作为早期检测的生物标志物。麻醉神经毒性。我们相信，通过我们最近在 NIH 资金支持下开创的鸟枪脂质组学技术，可以在脑损伤的早期阶段检测到麻醉暴露引起的脂质变化。这项技术的威力已在发现脑脊液和血浆中脂质的改变以及阿尔茨海默病脑组织的变化中得到证实。在该申请中，我们将利用现有研究项目的优势，在该项目中，我们在 FDA 的合作者正在对发育中的猴子模型中麻醉引起的神经元损伤进行研究，事实证明，这对于了解人类药理学方面具有无价的价值。我们的假设得到了初步研究的有力支持，初步研究表明，接触麻醉剂的猴子的大脑、脑脊液和血浆中的许多脂质类别发生了显着变化。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剂暴露的更早阶段（即较短的持续时间），与神经元细胞死亡增加和/或增加所揭示的变化相比。或基因表达的变化； (2)确定暴露于麻醉剂的猴子的脑脊液和血浆中的脂质改变发生在与检测到的脑组织中脂质含量和/或组成的变化平行的阶段； (3) 验证 暴露于麻醉剂的猴子的脑脊液和血浆中出现的脂质改变可以作为早期检测麻醉剂引起的神经毒性的生物标志物。拟议的研究对于发现一组特异性且敏感的脂质生物标志物具有巨大的希望，这些生物标志物可用于检测脑脊液和/或血浆中早期麻醉神经毒性，可用于未来的转化研究。这项研究还可能深入了解全身麻醉神经毒性的生化机制。