CPB Seminar Series: Webster Santos, Ph.D., Professor and College of Science Faculty fellow, Virginia Tech
"Blocking S1P Synthesis and Transport to Probe Sphingolipid Biology"
When |
Tuesday, November 19, 2024
12 to 1 p.m. PST
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---|---|
Where |
Campus:
Building:
3232 SW Research Drive
Portland,
Oregon
97239
M1441
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Contact Information |
Carsten Schultz
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To view the seminar recording, please use your OHSU login here.
Abstract
Sphingosine 1-phosphate (S1P) is a bioactive lipid that regulates the growth, survival, and migration of several cell types. S1P is synthesized intracellularly by sphingosine kinases (SphK1 and SphK2) and exported by Mfsd2b and Spns2. Extracellular S1P binds to G-protein coupled receptors S1PR1-5 to mediate a myriad cellular signals and implicated in a variety of pathologies including cancer, kidney fibrosis, and multiple sclerosis when S1P signaling goes awry. While the immunosuppressive activity of S1P1 receptor modulators (SRMs) has proved useful in treating autoimmune diseases such as multiple sclerosis and ulcerative colitis, the drug class is hampered by on-target liabilities such as initial dose bradycardia and vascular leak. We hypothesize that targeting upstream nodes of the S1P pathway may provide an improved adverse event profile. In this presentation, we will discuss the development of sphingosine kinase as well as Spns2 inhibitors, probe underlying S1P biology, provide a molecular basis for binding, characterize their activity both in vitro and in vivo, and demonstrate their efficacy in the EAE and kidney fibrosis mouse models.
Learn more about the Santos Lab here.