Structure and function of phospholipids and inositol phosphates in the nucleus.

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Summary: Phospholipids and inositol phosphates are two classes of small molecules with well-known functions in the cytoplasm, but poorly defined roles in the nucleus. The goal of my diverse group is to understand the structural biology and functional genomics of these two classes of small molecules. We also take chemical biology approaches to develop new small molecules to interrogate nuclear functions, which informs therapeutic development for several human diseases. Nuclear lipids are enigmatic molecules because they are found outside membranes, within the nucleoplasm and have metabolic and signaling properties distinct from membrane lipids. However, we do not understand fundamental aspects of the structure or function of nuclear lipids, which are ubiquitous, well conserved signaling molecules. Funding over the past 3.5 years has used the NR5A nuclear phospholipid receptors as models to address these questions. Those studies informed new approaches to small molecule screening for full-length NR5A2, the results of those screens revealed new molecules that regulate these receptors in new ways, which we build on here. Over the next five years, our studies will reveal the structures of ceramide, sphingomyelin and sphingolipid bound NR5A receptors, as well as new small molecules and genes that regulate nuclear lipid signaling through NR5As, enabling further progress. Nuclear inositol phosphates are soluble signaling molecules made by the nuclear kinase “inositol polyphosphate multikinase”, or IPMK. Work from several groups has established IPMK kinase activity regulates gene expression, however specific cellular mechanisms have remained unclear. Funding over the past 3.5 years used genetics in human cells to show IPMK-generated inositol phosphates specifically activate HDAC3 to regulate histone acetylation, further progress has been hampered by limitations inherent to these genetic knockout/complementation approaches. To overcome this, we helped develop the first selective chemical inhibitors of IPMK, which have revealed novel aspects of inositol phosphate signaling. Over the next five years, we can now use these inhibitors to ask questions not previously possible, defining how IPMK regulates transcription. Our group is uniquely positioned to address these diverse problems because we focus on two model systems: the NR5A nuclear phospholipid receptors and IPMK. We have developed novel chemical and genetic tools that give us unique ability to interrogate these difficult questions. Our work will reveal how phospholipids and inositol phosphates control gene expression, with potential to impact cancer, diabetes and the metabolic side effects of anti-psychotic drugs.