Imaging cholesterol metabolic flux and transport underlying brain function

中枢神经系统中的胆固醇通过血脑屏障与身体其他部分隔开。中枢神经系统中胆固醇合成、转运或代谢的紊乱与严重的神经和认知缺陷有关。虽然成年人大脑中的胆固醇水平处于稳定状态，但在从头合成和代谢之间存在着微妙的平衡。脑细胞一生都在合成胆固醇。越来越多的证据表明，不仅胆固醇的稳态浓度很重要，而且胆固醇前体和代谢物对有效的大脑活动也很重要，包括学习，记忆和运动功能。因此，通过胆固醇合成和代谢途径的代谢物的连续流动对于维持脑功能是必不可少的，并且测量这些途径中代谢物的空间通量将进一步了解胆固醇在适当脑功能中的参与。胆固醇的周转如何在不同的大脑区域不同，并随着年龄的变化也影响大脑功能尚不清楚。此外，目前还不清楚局部从头胆固醇生物合成和胆固醇相关分子的产生是否对成人神经发生至关重要，就像胚胎中的情况一样。在这个项目中，我们将开发“下一代”质谱成像技术来回答这些困惑。随着他汀类药物作为胆固醇生物合成抑制剂的使用越来越多，这项研究的结果将特别重要。

Cholesterol in the central nervous system is separated from the rest of the body by the blood brain barrier. Disturbances in the synthesis, transport or metabolism of cholesterol in the central nervous system are associated with severe neurological and cognitive defects. Although the level of cholesterol in adult brain is at a steady-state there is a continuous turnover with an exquisite balance between de novo synthesis and metabolism. Brain cells synthesise cholesterol throughout life. Mounting evidence suggest that not only is the steady-state concentration of cholesterol important, but that cholesterol precursors and metabolites are also critical for effective brain activity, including learning, memory and motor function. Therefore, a continuous flow of metabolites through the cholesterol synthesis and metabolic pathways is essential to maintain brain function and measuring the spatial flux of metabolites in these pathways will provide further insight into the involvement of cholesterol in proper brain function. How the turnover of cholesterol differs in distinct brain regions and varies with age also affecting brain function is unclear. Furthermore, it is not known if local de novo cholesterol biosynthesis and generation of cholesterol-related molecules is essential for adult neurogenesis, as is the case in the embryo. In this project we will develop "next generation" mass spectrometry imaging technologies to answer these quandaries. Results from this study will be particularly important with the growing use of the statin class of drugs as inhibitors of cholesterol biosynthesis.