Role and Function of Peroxisomal Ether Phospholipids in TBI

过氧化物酶体醚磷脂在 TBI 中的作用和功能

• 批准号: 10218660
• 负责人: Jace W Jones
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218660
• 关键词: Acute; Acyltransferase; Affect; Animals; Antioxidants; Attenuated; Autophagocytosis; Biochemical; Biochemical Process; Brain; Brain Injuries; Cause of Death; Cell Death; Cells; Cellular Membrane; Defect; Elderly; Enzymes; Functional disorder; Glycerol; Glyceryl Ethers; Goals; Health; Hippocampus (Brain); Impairment; In Vitro; Injury; Knockout Mice; Lesion; Lipids; Liquid Chromatography; Measures; Mechanics; Membrane; Membrane Lipids; Membrane Microdomains; Methods; Military Personnel; Modeling; Molecular; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuronal Injury; Neurons; Outcome; Oxidative Stress; Pathology; Phospholipid Ethers; Play; Population; Proteins; Recovery of Function; Regulation; Research; Role; Stretching; Structure; Supplementation; Testing; Time; Tissues; Traumatic Brain Injury; base; behavior test; cell injury; cognitive disability; cognitive function; disability; effective therapy; functional outcomes; injured; inorganic phosphate; insight; lipid metabolism; lipidomics; liquid chromatography mass spectrometry; mortality; neuron loss; neuroprotection; new therapeutic target; overexpression; peroxisome; physically handicapped; progressive neurodegeneration; tandem mass spectrometry; young adult

PROJECT SUMMARY Traumatic brain injury (TBI) is one of the major health concern affecting almost 1.7 million annually in the US. To date no effective therapy is available, mainly because of incomplete understanding of the molecular mechanisms of injury associated biochemical changes in the injured brain. In this study we aim to determine the role and function of ether phospholipids in neurodegeneration after TBI. Ether phospholipids play crucial role in maintaining structural integrity and protecting cellular membrane from oxidative stress. Their synthesis is initiated by the enzyme machinery of peroxisomes. Decreased level of ether phospholipids due to impaired peroxisomal functions have been demonstrated in different neurodegenerative diseases. However, their role in the pathophysiology of TBI has not been assessed. In this study our goal is to test the hypothesis that dysregulation of ether phospholipid abundance due to the impairment in peroxisomal ether phospholipid synthesis contributes to neuronal death after TBI. We will use liquid chromatography mass spectrometry (LC-MS/MS) based lipidomic approach to determine the changes in ether phospholipids in the whole cortical tissues of TBI mice. We will also determine the levels of ether phospholipid precursors in the peroxisomal fractions isolated from mouse cortices after TBI to assess peroxisomal ether phospholipid synthesizing function in the injured cortices. We will also use in vitro neuronal stretch injury model to investigate the mechanisms of dysregulation in ether phospholipid abundance and its role in neuronal death after injury. In AIM 1, we will investigate the mechanisms of dysregulation in ether phospholipid and its role in neuronal death after TBI in mice. LC-MS/MS based lipidomic analysis combined with biochemical methods will be used to test the hypothesis that peroxisomal ether phospholipid synthesis is impaired in the mouse brain after TBI causing decrease in ether phospholipid abundance that contributes to neuronal death in the injured brain. In AIM 2, we will determine the neuroprotective functions of ether phospholipid precursor supplementation in TBI mice. We hypothesize that increase in ether phospholipid abundance will attenuate injury associated neuronal death and will restore motor and cognitive functions in TBI mice. We will treat TBI mice with ether phospholipid precursor – 1-O-alkyl glycerol and assess its neuroprotective functions by measuring the extent of neuronal death and functional recovery in those mice. Our study will for the first time determine the role and function of ether phospholipids in TBI. We believe that this study will provide new mechanistic insight about TBI associated neuronal death and thus may help us to identify novel therapeutic target to treat TBI.

项目概要 创伤性脑损伤 (TBI) 是每年影响近 170 万人的主要健康问题之一 迄今为止，美国尚无有效的治疗方法，主要是因为对分子的了解不完全。 在这项研究中，我们的目的是确定受伤大脑中与损伤相关的生化变化的机制。 醚磷脂在 TBI 后的神经退行性变中发挥着至关重要的作用。 它们的合成是维持结构完整性和保护细胞膜免受氧化应激的作用。 由过氧化物酶体的酶机制引发，由于受损而导致醚磷脂水平降低。 过氧化物酶体的功能已在不同的神经退行性疾病中得到证实，但它们在疾病中的作用。 TBI 的病理生理学尚未得到评估，在本研究中，我们的目标是检验以下假设： 由于过氧化物酶体醚磷脂受损而导致醚磷脂丰度失调 合成导致 TBI 后神经元死亡。 我们将使用基于脂质组学方法的液相色谱质谱法 (LC-MS/MS) 来确定 我们还将测定 TBI 小鼠整个皮质组织中醚磷脂的水平。 TBI 后从小鼠皮质中分离出的过氧化物酶体组分中的醚磷脂前体进行评估 过氧化物酶体醚磷脂在受损皮质中的合成功能我们还将使用体外神经元。 拉伸损伤模型研究醚磷脂丰度失调的机制及其作用 在 AIM 1 中，我们将研究乙醚失调的机制。 基于 LC-MS/MS 的脂质组学分析结合磷脂及其在小鼠 TBI 后神经元死亡中的作用。 将用生化方法来检验过氧化物酶体醚磷脂合成是的假设 TBI 后小鼠大脑受损，导致乙醚磷脂丰度下降，从而导致 在 AIM 2 中，我们将确定乙醚的神经保护功能。 我们在 TBI 小鼠中补充磷脂前体，以增加乙醚磷脂含量。 丰度将减轻损伤相关的神经元死亡，并恢复 TBI 中的运动和认知功能 我们将用醚磷脂前体 - 1-O-烷基甘油治疗 TBI 小鼠并评估其神经保护作用。 通过测量这些小鼠的神经死亡和功能恢复的程度来发挥功能。 我们相信，我们的研究将首次确定醚磷脂在 TBI 中的作用和功能。 这项研究将为 TBI 相关神经死亡提供新的机制见解，从而可能帮助我们 确定治疗 TBI 的新治疗靶点。

项目成果

Glycerophospholipid dysregulation after traumatic brain injury.

脑外伤后甘油磷脂失调。

• 发表时间: 2024-05
• 影响因子: 4.2
• 作者: Sarkar, Chinmoy;Lipinski, Marta M
• 通讯作者: Lipinski, Marta M