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 (PIPs), 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 are currently seven major projects ongoing in the lab:

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1) Determine if eukaryotic chromatin recruits lipid signaling enzymes using chromatin immunoprecipitation and genomic expression analyses (Beth and Ray).

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2) Determine structure-function realtionships of full-length nuclear receptors and signaling kinases using integrated structural biology, X-ray crystallography and NMR (Corey and Merced).

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3) Determine how the phosphoinositide PIP3 regulates the structure and function of the nuclear receptor SF-1, using a combination of x-ray crystallography and peptide-binding assays (Harry and Katrina).

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4) Develop new classes of therapeutics in collaboration with the Vanderbilt HTS Facility, using novel nuclear receptor screening assays and kinase inhibitor screens (Merced and Sophie).

5) Correlate novel environmental & social factors influencing liver cancer prevalence using the Vanderbilt Synthetic Derivative and gene expression analysis (Meredith and Grayson).

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6) 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 (Beth and Ray).

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7) Quantitate how phospholipids are transferred to membranes by NR5A nuclear receptors using biophysical analyses such as crystallography, lipid transfer assays, and fluorescence polarization (You! and Ray).

The Journal of Biological Chemistry Herb Tabor Award to Ray Blind Vanderbilt University.
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National Cancer Institute Transition to Indepedence Award to Ray Blind Vanderbilt University
National Institute of General Medical Sciences Institutional Research and Career Development Fellowship to Ray Blind, Vanderbilt University
Vanderbilt Diabetes Research and Training Center
Vanderbilt Ingram Cancer Center
Vanderbilt Institute of Chemical Biology
Vanderbilt Center for Structural Biology
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© 2019  Ray Blind