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.

项目总结