CROSS TALK BETWEEN THE SPHINGOLIPID AND FOLATE PATHWAYS

这个子项目是众多研究子项目之一

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 underlying molecular mechanisms. Specifically, we propose to evaluate the role of sphingolipid signaling in mediation of the effects of folate deficiency and the disturbance of intracellular folate metabolism. The modern biomedical science lacks the studies, which would investigate functional interactions between the folate and sphingolipid pathways. 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/histones methylation), while folates are crucial for cellular methylation; (3) cross-talk between the two pathway is suggested by experiments with fumonisine, an inhibitor of ceramide synthase, and antifolates; (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 down-stream effect of the folate stress. The alteration of methylation in sphingolipid pathways is proposed as the underlying mechanism in this process. Aims to test the hypotheses are: Aim 1. Determine effects of folate deficiency on sphingolipid pathways. Aim 2. Explore the role of folate-dependent methylation in sphingolipid pathways. Aim 3. To determine whether ceramide signaling is a component of cellular response to impaired folate metabolism.