BPS-ASPET Symposium: A Current Perspective of Sphingolipid Signaling as a Therapeutic Target

Thursday April 29, 2021

10:00 am - 11:30 am Eastern Time (ET)

View session on the EB Virtual Platform (EB registration required)

DCP DMDD MP TOX

Chair :

Simon Kennedy
University of Glasgow

Kenneth Watterson
University of Glasgow



Co-sponsored by the British Pharmacological Society.

The sphingolipid system has an increasingly important role in a wide range of conditions and diseases, such as cancer, cardiovascular disease, diabetes and multiple sclerosis. Biological targets such as sphingosine kinase, sphingosine-1-phosphate (S1P) receptors and S1P lyase are therefore being actively pursued by academics and pharmaceutical companies in an attempt to develop better drugs for the treatment of these conditions. World-leading researchers, including Professor Sarah Spiegel, the discoverer of the S1P molecule, will give a current perspective on the field, with an emphasis on the molecular and cellular mechanisms that underpin sphingolipid-targeted therapy. This symposium is co-sponsored by ASPET and the British Pharmacological Society.

Speakers

Sarah Spiegel - Virginia Commonwealth University

My Journey with Sphingosine-1-phosphate

The bioactive lipid mediator, sphingosine-1-phosphate (S1P), has a crucial role in a broad range of cellular functions. In this presentation, Professor Sarah Spiegel, the discoverer of S1P, will provide a personal reflection on her research with S1P.

Nigel Pyne - University of Strathclyde

Therapeutic Targeting of Sphingosine Kinases in Disease

Sphingosine kinase (two isoforms, SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and play a key role in health and disease. Each isoform has a predominant role in a disease-specific manner, such as in cancer, fibrosis and psoriasis. Therefore, it is important to develop isoform-specific inhibitors that can be translated to new medicines. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding ‘J-channel’. Relatively conservative changes in compound structure can be used to change the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency. In addition, we have previously suggested that SK1 adopts a dimeric quaternary structure in which the alignment of contiguous hydrophobic and positively charged areas produces translocation from the cytoplasm and high-affinity attachment to the plasma membrane, required for activation of the kinase. A model involving release of a translocation brake and N-terminal/C-terminal inter-domain movement to enable translocation is proposed. These new aspects of the structure/function of SK1 provide novel avenues for drug development designed to block translocation and activation of SK1 in disease.

Herve Le Stunff - Universitie Paris-Saclay

Brain Ceramide Metabolism in the Control of Glucose Homeostasis

A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases such as insulin resistance, steatohepatitis and type 2 diabetes. Recent data have reported that, similar to what is observed in peripheral tissues, hypothalamic lipotoxicity could be mediated by complex lipids such as ceramides and sphingolipids, resulting in the dysregulation of energy and glucose homeostasis and favour obesity and type 2 diabetes. This presentation will review what is currently known about hypothalamic sphingolipid metabolism and the modulation of energy/glucose homeostasis.

Paola Giussani - University of Milan

Ceramide and Sphingosine-1-phosphate in Glioblastoma Cell Survival and Invasiveness

Different sphingolipid metabolites, such as ceramide (Cer), and sphingosine-1-phosphate (S1P), have emerged as active mediators involved in the control of different physio- and pathological cell behavior included tumors such as gliomas. The inhibition of Cer (an oncosuppressor molecule) accumulation in the cells as well as the activation of S1P (an oncopromotor molecule) signalling have been implicated in invasiveness,drug-resistance, and escape from cell death. Altogether these informations can have important implications for Cer- and S1P-based therapy of gliomas and provide a basis for further investigations to overcome cell death resistance and invasiveness in glioma cells

Last Updated: February 8, 2021
Key Dates
 
April 27 – 30, 2021

ASPET Annual Meeting at EB 2021

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