The NR5A nuclear receptors NR5A1 (Steroidogienic Factor-1, SF-1) and NR5A2 (Liver Receptor Homolog-1, LRH-1) activate genetic programs that are essential determinants of development, differentiation and adult physiology in the liver, pancreas, adrenals and gonads.
At the molecular level, NR5As bind phosphoinositides, which are small signaling phospholipids essential in PTEN-dependent cancers. We recently uncovered a novel mechanism that these phospholipids & their signaling enzymes use to regulate NR5As. This mechanism links dysregulation of these new signaling pathways to PTEN-dependent cancers.
Our central hypothesis is that lipids bound to nuclear proteins are directly remodeled by lipid signaling enzymes, namely the PI3-kinase inositol polyphosphate multikinase (IPMK) and the PTEN lipid phosphatase. This hypothesis is a clear departure from the standard dogma that PI3-kinases & PTEN can only act on phospholipids in membrane systems.
Thus, our group is interested in understanding how non-membrane lipids store biological information, and how that information is decoded to appropriately regulate cellular physiology.
This broad interest manifests itself differently depending on the interests of each scientist in our group. Each group member is encouraged to follow their own unique scientific curiosities, regardless of what path it leads them on. This scientific diversity is intentionally designed, leading to unexpected discoveries that can revolutionize entire fields. By exposing data to an interdisciplinary set of diverse eyes, we can each better contextualize our data and maximize the impact of our discoveries.
There have been eight major projects ongoing in the lab:
HDAC3 bound to IP4
(John Schwabe Lab).
IPMK-dependent transcript changes
1) Determine if eukaryotic chromatin recruits lipid signaling enzymes using chromatin immunoprecipitation and genomic expression analyses (Pratima & Hundaol).
2) Determine structure-function realtionships of nuclear receptors and signaling kinases using integrated structural biology, X-ray crystallography and computational drug docking (Ana & Claire).
3) Determine how phospholipids regulate the structure & function of nuclear receptors SF-1 and LRH-1, using a combination of x-ray crystallography, cross-linking mass spectrometry, computational docking and other biophysical approaches (Alexis & Alex).
4) Establish nuclear phosphoinositides interact with NR5A nuclear receptors in vivo, and distinguish between interactions between the PIP2 and PIP3 phosphoinositides (Jessica & Aleshia).
5) Determine quantitative differences at the ligand binding sites of NR5A nuclear receptors which influence drug binding, using in silico computational small molecule docking (Ana & Claire).
6) Correlate novel environmental & social factors influencing liver cancer prevalence using the Vanderbilt Synthetic Derivative and gene expression analysis (Ray & Meredith).
7) Develop new classes of therapeutics in collaboration with the Vanderbilt HTS Facility, using novel nuclear receptor screening assays and kinase inhibitor screens (Kimora & Alexis).
8) Determine how structure-based mutations in nuclear receptors change gene expression patterns in human cell lines. These engineered mutations were designed based on our new structure of fulll-length LRH-1 (Jessica & Kimora).