Description:

Please join the Department of Pharmacology for a Works-in-Progress presentation.

Brittany Hopkins, Graduate Student in the Laboratory of Dr. Richard Miller

"Characterization of Novel Small Molecule Ligands for the Chemokine Receptor CXCR7”

One of the most widely studied chemokines is stromal-derived factor (SDF-1) which has two cognate GPCRs: CXCR4 and CXCR7. CXCR7 is atypical in that it does not couple with G-proteins instead acting through the b-arrestin signaling pathway. Our lab had previously generated a series of small molecule ligands for the CXCR4 receptor and I will discuss my work characterizing these small molecules as potential CXCR7 ligands. To pharmacologically characterize these potential novel ligands, we have utilized a variety of techniques including: assessment of b-arrestin signaling, receptor internalization, and receptor mutagenesis. This has led to the identification of a novel class of CXCR7 agonists. Characterizing these novel small molecule ligands will provide us with powerful pharmacological probes to better understand the physiological roles of the SDF-1/CXCR4/CXCR7 signaling axis.

Erin Baker, Graduate Student in the Laboratory of Dr. Jennifer Kearney

"GS967 Treatment in a Mouse Model of SCN8A Encephalopathy”

Over 100 de novo mutations in SCN8A have been associated with infantile-onset encephalopathy that includes seizures, delays in cognitive and motor development and increased risk of sudden unexpected death in epilepsy (SUDEP). Functional characterization of mutations demonstrated that elevated persistent current is a common defect. A mouse model carrying the N1768D gain-of-function mutation recapitulates many features of the patient phenotype, including spontaneous seizures and reduced lifespan. High-dose phenytoin has been reported as beneficial for seizure control in some individuals with SCN8A mutations, but the narrow therapeutic window of phenytoin is a concern. Additional drugs that preferentially block persistent current could benefit this patient population. GS967 is a sodium channel blocker with greater potency and enhanced preference for suppressing persistent current compared to phenytoin. Electrophysiology studies demonstrated that elevated persistent current in neurons from untreated Scn8a-N1768D/+ mice was attenuated by acute application of GS967. Chronic treatment of Scn8a-N1768D/+ mice with GS967 rescued the premature lethality, with 100% surviving to 6 months of age compared to 20% of untreated. The beneficial effect was lost upon withdrawal of GS967 chow. Treatment with GS967 extended survival of homozygous Scn8a-N1768D/N1768D mice, with 50% of treated mice surviving for 4 weeks compared to none of the untreated mice. Chronic GS967 administration prolonged survival of Scn8a-N1768D mice, which may be due to suppression of aberrant persistent sodium current in neurons. This study demonstrates a beneficial effect of GS967 in a mouse model of SCN8A encephalopathy and provides further support for GS967 as a novel anticonvulsant for refractory epilepsies.