RO1NS118020 Research Supplements to Promote Diversity in Health-Related Research

RO1NS118020 促进健康相关研究多样性的研究补充剂

• 批准号: 10622090
• 负责人: HAESUN A KIM
• 金额: $ 6.22万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622090
• 关键词: Affect; Anabolism; Applications Grants; Biochemical; Carrier Proteins; Cells; Choline; DNA Methylation; DNA Modification Process; Demyelinating Diseases; Development; Epigenetic Process; Exhibits; Funding; Gene Expression; Genetic; Health; Impairment; Lecithin; Lipids; Membrane; Metabolism; Molecular; Myelin; Neuroglia; Oligodendroglia; Parents; Peripheral; Phosphatidylinositols; Phospholipids; Positioning Attribute; Regulation; Reporting; Research; S-Adenosylmethionine; Schwann Cells; Signal Transduction; Techniques; Testing; Therapeutic; base; choline transporter; design; disease prognosis; early onset; epigenetic regulation; histone methylation; improved; in vivo; insight; myelination; nervous system disorder; parent grant; patient prognosis; repaired; tool

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.

摘要 细胞合成胆碱的能力有限，因此细胞依赖于蛋白质转运蛋白来输入 胆碱胆碱用于合成磷脂酰胆碱，髓鞘的结构脂质组分由磷脂酰胆碱合成。 合成了磷脂酰胆碱也被代谢以产生磷脂酰肌醇，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（SAM）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，我们对胆碱输入和胆碱- 在髓鞘形成的神经胶质细胞中依赖代谢。髓鞘形成神经胶质细胞的胆碱转运蛋白尚未被发现。 鉴定 我们已经确定胆碱样转运蛋白1（CTL 1）作为一个重要的调节许旺细胞髓鞘。 雪旺细胞中的CTL 1缺失（CTL 1 sc-KO）导致PNS中局灶性髓鞘形成的早期发作。 生化分析显示，在髓鞘胆碱衍生的磷脂的整体下降。此外，委员会认为， CTL 1缺失损害髓鞘基因表达，并在雪旺细胞中表现出改变的DNA修饰。母 格兰特的建议，这一补充测试的假设，CTL 1是一个雪旺细胞胆碱转运。与 最后，我们目前正在测试三个目的，以确定：1）CTL 1是否作为胆碱转运蛋白在 雪旺细胞，2）CTL 1是否有助于PNS中的磷脂酰肌醇信号传导和3）CTL 1是否 损失影响雪旺细胞的遗传和表观遗传谱。 使用现有的工具和实验技术，从母研究，拟议的研究在此 研究补充旨在测试CTL 1作为胆碱转运蛋白的假设， 少突胶质细胞这是基于以前的报道和我们最近的发现，即CTL 1在 在少突胶质细胞分化过程中，其表达增加。Adriana托雷斯女士 将得到补充资金的支持，将进行两个具体目标，这将决定1）CTL 1 在少突胶质细胞中作为胆碱转运蛋白发挥作用，2）体内CTL 1缺乏是否影响 少突胶质细胞发育和髓鞘形成。这项研究的结果预计将提供重要的见解 了解胆碱转运及其代谢在髓鞘形成神经胶质细胞中的功能。