Dynamics of lipids and cerebral metabolism after injury and during recovery in the central nervous system

血脂在中枢神经系统（CNS）中具有重要的结构作用。中枢神经系统损伤会诱发一些过程的激活，这些过程会破坏膜脂（如甘油磷脂）的稳定性，并诱发有害的氧化变化[Nessel和Michael-Titus，2021]。脂质不稳定是磷脂酶活化的结果。我们和其他人已经提出，抑制磷脂酶可以限制CNSinjury的影响[Huang et al . 2009；Sarkar等人；2020]。然而，对于特定磷脂酶的作用以及损伤后和恢复过程中甘油磷脂的变化，人们的理解仍然不完整。损伤还会引发组织氧化，从而引起连锁反应过程和大规模的膜退化。氧化和神经炎症协同作用，增加组织损伤。最近氘化脂质的可用性使得通过将其用作抗氧化剂来研究阻断氧化的影响成为可能-在神经变性模型中报道的结果很有希望[Raefsky等人，2018]。我们将重点关注：1。甘油磷脂的变化和特定磷脂酶的靶向性；使用氘化脂肪酸来阻止氧化。使用的模型将是小鼠和大鼠的皮质撞击造成的脑损伤。我们将通过成像和神经学结果确定组织中体外脂质/代谢组学的变化，并评估体内脑代谢和神经炎症[Tremoleda等人，2016]。我们将描述胞质磷脂酶A2的影响，使用选择性抑制剂（与德国MatthiasLehr教授合作）与使用有限选择性抑制剂（如先前使用的花生四烯基三氟甲基酮）进行比较。我们还将分析组织脂质的氧化，并在损伤后通过部分替代饮食中不含氘形式的脂肪酸进行干预，并研究对恢复的影响。Michael-Titus教授在神经损伤方面具有专业知识，特别是使用脂肪酸进行保护和修复。Lopez-Tremoleda博士在成像方面有专长。

TBCLipids have essential structural roles in the central nervous system [CNS]. CNS injury inducesan activation of processes which destabilise membrane lipids such as theglycerophospholipids, and induces deleterious oxidative changes [Nessel and Michael-Titus,2021]. Lipid destabilisation is a consequence of the activation of phospholipases. It has beensuggested by us and others that inhibition of phospholipases could limit the impact of CNSinjury [Huang et al 2009; Sarkar et al; 2020]. However, there is still incomplete understandingof the role of specific phospholipases and of changes in glycerophospholipids post-injury andduring recovery. Injury can also trigger tissue oxidation which induces chain-reactionprocesses and large-scale membrane deterioration. Oxidation and neuroinflammationsynergise and increase tissue damage. The recent availability of deuterated lipids has madeit possible to investigate the impact of blocking oxidation through their use as antioxidants -results reported in neurodegeneration models are promising [Raefsky et al, 2018].We will focus on: 1. Changes in glycerophospholipids and targeting of specificphospholipases, and 2. Use of deuterated fatty acids to block oxidation. The model used willbe a brain injury by cortical impact in mice and rats. We will determine lipid/metabolomicchanges ex vivo in tissue and assess in vivo cerebral metabolism and neuroinflammation[Tremoleda et al., 2016] using imaging, and neurological outcome. We will characterize theimpact of cytosolic phospholipase A2, using selective inhibitors -collaboration Prof MatthiasLehr, Germany - as compared with the use of an inhibitor with limited selectivity, e.g.arachidonyl trifluoromethylketone, used previously. We will also analyse the oxidation oftissue lipids and intervene post-injury with a partial replacement of dietary fatty acids withdeuterated forms and study the impact on recovery.Professor Michael-Titus has expertise in neurotrauma and in particular the use of fatty acidsfor protection and repair. Dr Lopez-Tremoleda has expertise in imaging.