P8 - AG Hermann Tanja Hussner

Role of ceramide-rich macrodomains in regulating ABC transporters post ischemia

Worldwide, cerebrovascular incidents like stroke are the second leading cause of death and the third leading cause of disabilities. Ischemic stroke, the sudden death of brain cells due to lack of oxygen caused by blockage or rupture of an artery and thereby attenuating blood flow to the brain, is also a leading cause of dementia and depression. Following ischemic injury, angiogenesis is required for reestablishment of blood and nutrient supply of the brain. A regulator of angiogenesis is the sphingolipid sphingosine-1-phosphate (S1P) which can be secreted from cells and transported extracellularly. S1P is generated from sphingosine by sphingosine kinase. Sphingosine in turn is generated by the catabolism of ceramide which can derive from de novo synthesis or conversion of sphingomyelin by sphingomyelinases.

The therapeutic potential of modulating S1P receptors is utilized in treatment of multiple sclerosis patients with the S1P receptor inhibitor Fingolimod (GilenyaTM, FTY720-P) where it leads to improved relapse rate and risk of disability progression. Fingolimod, systemically applied, acts as a functional antagonist of S1P1 leading to internalization and degradation of the receptor preventing T cell egress from lymph nodes. In addition, FTY720 improves neurological outcome in a mouse model of stroke and leads to reduced lesion size.

In general, the balance between ceramide and S1P seems to play a crucial role in controlling cell fate. Therapeutic interventions were already successful in patients with multiple sclerosis and depression disorders.

This thesis aims to determine the effects of other potential mechanisms influencing the Asm/ceramide system to gain insight into the potential neuroprotective mechanisms of this system.