Corey D. Seacrist - PhD Student, Vanderbilt Quantitative Chemical Biology Program
NIH Predoctoral Fellow, T32 DK007563 Molecular Endocrinology Training Grant
Chemical genetic and structural approaches to understanding nuclear lipid signaling.
Hometown - Charleston, SC
B.S. Biochemistry College of Charleston, SC
B.S. Molecular Biology College of Charleston, SC
B.A. Chemistry, Minor in Math College of Charleston, SC
MBA Master of Business Admin College of Charleston, SC
Intern Technology Transfer Medical University of South Carolina
Ph.D. Pharmacology Vanderbilt University School of Medicine
See Corey's Publications on PubMed
Recent studies estimate ~40% of the U.S. population is obese, constituting ~$200 billion in annual medical costs. Obesity is a major risk factor for cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD), all of which have dysregulated glucose and lipid homeostasis. Liver Receptor Homolog-1 (LRH-1) is a nuclear hormone receptor that regulates diverse cellular processes including hepatic glucose, cholesterol, and bile acid homeostasis. Structural studies of the ligand-binding domain in isolation revealed LRH-1 is capable of binding a diverse array of phospholipids, including the exogenous plant 12-carbon fatty- acid agonist dilauroylphophatidylcholine (DLPC). Treatment of diet-induced obese mice with DLPC was shown to increase liver bile acids, lower hepatic triglycerides and serum glucose, decrease hepatic steatosis and improve glucose homeostasis in an LRH-1 dependent manner.
Despite identification of DLPC as an agonist of LRH-1, no LRH-1 targeted therapies have reached the clinic for treatment of metabolic disorders. This may be in part due to a lack of structural information on how LRH-1 is activated in the context of the intact receptor as it is a monomer in contrast to classical dimeric nuclear receptors. Indeed, LRH-1 is post-translationally activated (phosphorylation) and inhibited (SUMOylation) in its hinge region, suggesting the hinge region is important for activation and repression of LRH-1 transactivation. We hypothesize there is interdomain crosstalk within LRH-1 and propose to use a combination of solution structure techniques to model its multi-domain organization.
Despite much effort to crystallize full-length LRH-1, no structure has been deposited into the PDB. Thus, previous studies have focused on the ligand binding domain (LBD) and DNA-binding domain in isolation (DBD). Taking a pragmatic approach, I propose to use a combination of non-crystallographic biophysical analyses to develop a model of the relative position of each domain to each other. LRH-1 will be independently phosphorylated or SUMOylated to test if post-translational modification induces large-scale conformational changes in the LRH-1/DNA complex. Further, LRH-1 will be phosphorylated or SUMOylated to determine which amino acids change conformation upon activation or inhibition of the receptor. Regions hypothesized to modulate domain-domain movement will be genetically perturbed and tested in cell-based gene expression assays.