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

TBCLipid在中枢神经系统[CNS]中具有重要的结构作用。中枢神经系统损伤导致破坏膜脂如甘油磷脂稳定的过程的激活，并诱导有害的氧化变化[Nessel和Michael-Ttus，2021]。脂类的不稳定是磷脂酶激活的结果。我们和其他人已经提出，抑制磷脂酶可以限制CNS损伤的影响[Huang等人2009年；Sarkar等人；2020年]。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仍有不完全的了解。损伤还可以触发组织氧化，从而导致连锁反应过程和大规模的细胞膜恶化。氧化和神经炎症协同作用，增加组织损伤。最近氢化脂质的可获得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--在神经退化模型中报道的结果是有希望的[Raefsky等人，2018]。我们将集中在：1.甘油磷脂的变化和特定磷脂酶的靶向，以及2.使用氚脂肪酸来阻断氧化。所使用的模型将是小鼠和大鼠大脑皮质撞击造成的脑损伤。我们将在体外确定组织中的脂质/代谢变化，并使用成像和神经学结果来评估体内的脑代谢和神经炎症[Tremoleda等人，2016]。我们将使用选择性抑制剂--德国的Matthias Lehr教授--与使用选择性有限的抑制剂(如先前使用的花生四烯基三氟甲基酮)相比，表征胞液磷脂酶A2的影响。我们还将分析组织脂类的氧化情况，并在损伤后用部分代之的饮食脂肪酸进行干预，并研究其对康复的影响。迈克尔-提图斯教授在神经创伤方面有专长，尤其是在使用脂肪酸进行保护和修复方面。洛佩兹-特雷莫里达博士在成像方面拥有专业知识。

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.