RO1NS118020 Research Supplements to Promote Diversity in Health-Related Research

摘要 细胞合成胆碱的能力有限，因此细胞依赖蛋白质转运体输入。 胆碱。胆碱用于合成磷脂酰胆碱，髓鞘的结构脂肪成分是由磷脂酰胆碱 合成的。磷脂酰胆碱也被代谢生成磷脂酰肌醇，其磷酸化 衍生物是调节髓鞘形成的重要信号脂质。胆碱参与合成 通用甲基供体S-腺苷甲硫氨酸用于组蛋白和DNA甲基化，从而调节基因 表情。考虑到胆碱在磷脂生物合成的十字路口的位置 表观遗传调控，我们对胆碱进口和胆碱的调控知之甚少。 髓鞘胶质细胞的依赖代谢。髓鞘形成神经胶质细胞的胆碱转运体尚未被 已确认身份。 我们发现类胆碱转运蛋白1(CTL1)是雪旺细胞髓鞘形成的重要调节因子。 雪旺细胞CTL1缺失(CTL1sc-KO)可导致PNS早期出现局灶性超髓鞘形成。 生化分析显示髓鞘中胆碱衍生的磷脂总体减少。此外， CTL1缺失会损害雪旺细胞髓鞘基因的表达，并表现出DNA修饰的改变。父级 这项补充的建议验证了CTL1是雪旺细胞胆碱转运体的假设。到那时候 最终，我们目前正在测试三个目标以确定：1)CTL1是否在 雪旺细胞，2)CTL1是否参与三叉神经节的磷脂酰肌醇信号转导，以及3)CTL1是否参与PNS中的磷脂酰肌醇信号转导 雪旺细胞的缺失影响遗传和表观遗传学特征。 利用母体研究中可用的工具和实验技术，本研究中拟议的研究 研究补充旨在检验CTL1在脑内作为胆碱转运体的作用的假设 少突胶质细胞。这是基于之前的报告和我们最近的发现，CTL1在 少突胶质细胞及其表达在少突胶质细胞分化过程中增加。Adriana Torres女士，她 在补充资金上将得到支持，将进行两个具体的目标，这将决定1)CTL1 在少突胶质细胞中作为胆碱转运体的功能以及2)体内CTL1缺乏是否影响 少突胶质细胞发育和髓鞘形成。研究结果有望提供重要的见解 了解胆碱在髓鞘形成的神经胶质细胞中的转运和代谢功能。

ABSTRACT Cells have a limited capacity to synthesize choline, thus cells depend on protein transporters to import choline. Choline is used to synthesize phosphatidylcholine, from which structural lipid components of myelin are synthesized. Phosphatidylcholine is also metabolized to generate phosphotidylinositols, whose phosphorylated derivatives are important signaling lipids that regulate myelination. Choline is involved in synthesis of the universal methyl donor, S-adenosylmethionine (SAM) for histone and DNA methylation, thus regulating gene expression. Considering the position of choline at the crossroad for the biosynthesis of phospholipids and epigenetic regulation, we have very little to no understanding of the regulation of choline import and choline- dependent metabolism in myelinating glial cells. Choline transporters for myelin-forming glial cells have not been identified. We have identified choline-like-transporter 1 (CTL1) as an important regulator of Schwann cell myelination. CTL1 deletion in Schwann cells (CTL1sc-KO) results in early onset of focal hyper-myelination in the PNS. Biochemical analysis revealed an overall decrease in choline-derived phospholipids in the myelin. Furthermore, CTL1 loss impaired myelin gene expression and exhibited altered DNA modifications in Schwann cells. Parent grant proposal of this supplement test the hypothesis that CTL1 is a Schwann cell choline transporter. To that end, we are currently testing three aims to determine: 1) whether CTL1 functions as a choline transporter in Schwann cells, 2) whether CTL1 contributes to phosphatidylinositol signaling in the PNS and 3) whether CTL1 loss impact genetic and epigenetic profiles in Schwann cells. Using the available tools and experimental techniques from the parent study, the proposed study in this Research Supplement is designed to test the hypothesis that CTL1 functions as a choline transporter in oligodendrocytes. This is based on previous reports and our recent findings that CTL1 is highly expressed in oligodendrocytes and its expression increased during oligodendrocyte differentiation. Ms Adriana Torres, who will be supported on the supplement funds, will carry on two specific aims that will determine 1) whether CTL1 functions as a choline transporter in oligodendrocytes and 2) whether CTL1-deficiency in vivo impacts oligodendrocyte development and myelination. Results from the study are expected to provide important insights into understanding the function of choline transport and its metabolism in myelin-forming glial cells.