CROSS TALK BETWEEN THE SPHINGOLIPID AND FOLATE PATHWAYS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 本项目的主要目的是建立叶酸和鞘脂途径之间的功能联系，并探索潜在的分子机制。具体而言，我们建议评估鞘脂信号转导的作用，在调解叶酸缺乏的影响和响应细胞内叶酸代谢紊乱。 目前，缺乏关于叶酸和鞘脂途径之间的功能相互作用的知识，但有具体的迹象表明，这两种途径在功能上是相连的。(1)它们都依赖丝氨酸作为叶酸库的主要一碳基团供体和鞘脂从头合成的底物;（2）鞘脂途径直接依赖于甲基化（磷脂酰乙醇胺甲基化为磷脂酰胆碱）和间接（通过DNA/组蛋白甲基化调节酶表达），而叶酸对细胞甲基化至关重要;（3）用伏马新碱（fumonisine）（一种血清酰胺合成酶抑制剂）以及用阿替叶酸盐（atifolates）进行的实验表明，这两种途径之间存在相互作用;（4）我们的研究表明，细胞内叶酸盐代谢改变时，神经酰胺水平发生显著变化。 因此，我们假设鞘脂途径的激活是叶酸应激的下游事件。 在这个过程中的甲基化的改变spingolipid途径提出的潜在机制。 测试这个假设的目的是：目的1。确定叶酸缺乏对鞘脂途径的影响。目标2.探索叶酸依赖性甲基化在鞘脂途径中的作用。目标3。确定神经酰胺信号传导是否是对叶酸代谢的细胞反应的一个组成部分。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main objective of this project is to establish the functional connection between folate and sphingolipid pathways and to explore the underlying molecular mechanisms. Specifically, we propose to evaluate the role of sphingolipid signaling in mediation of the effects of folate deficiency and responces to the disturbance of intracellular folate metabolism. At present, there is a lack of knowledge regarding the functional interactions between the folate and sphingolipid pathways, but there are specific indications that the two pathways are functionally connected. (1) They both rely on serine as the principal one-carbon group donor into the folate pool and a substrate for de novo sphingolipid biosynthesis; (2) sphingolipid pathways depend on methylation directly (methylation of phosphatidylethanolamine to phosphatidylcholine) and indirectly (regulation of enzyme expression via DNA/histone methylation), while folates are crucial for cellular methylation; (3) cross talk between the two pathway is suggested by experiments with fumonisine, an inhibitor of seramide synthase, as well as in experiments with atifolates; (4) our studies have demonstrated significant changes in the levels of ceramides upon alterations of intracellular folate metabolism. Therefore we have hypothesized that activation of sphingolipid pathways is the downstream event of the folate stress. The alteration of methylation in spingolipid pathways is proposed as the underlying mechanism in this process. Aims to test this hypothesis are: Aim 1. Determine effects of folate deficiency on sphingolipid pathways. Aim 2. Explore the role of folate-dependent methylation in spingolipid pathways. Aim 3. Determine, whether ceramide signaling is a component of cellular response to impared folate metabolism.