Project Description Project Description

Christina Voelkel-Johnson

Pilot Project Awarded 2016

The Role of CerS6 in Colitis

The balance between inflammatory IL-17 secreting T cells and suppressive T regulatory cells is critical for maintaining immune homeostasis. A key difference between these T cell subsets with opposing function is their energy metabolism. Inflammatory T cells use the glycolyticlipogenic pathway, whereas suppressive T regulatory cells rely on mitochondrial fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC1) functions as a central switch between these metabolic pathways. We hypothesize that CerS6-deficiency leads to an accumulation of its substrate palmitoyl-CoA resulting in compensatory upregulation of FAO and/or inhibition of ACC1. Increased utilization of lipids in the liver and adipose tissue in CerS6 KO mice supports this hypothesis. We further predict that the consequence of this key metabolic difference is the preferential development of suppressive T regulatory cells. Our preliminary data suggest that CerS6 KO mice are more tolerant to colitis and have fewer splenic inflammatory CD8 T cells, which is consistent with a subdued inflammatory response.  Our long-term goal is to understand the influence of sphingolipid metabolism on the immune system, which would lay the foundation for the development of novel therapeutic strategies for immune disorders.


Pilot Project Awarded 2013

Programmed cell death or apoptosis is a mechanism crucial for elimination of aberrant cells that contribute to the development of disease such as autoimmune disorders or cancer as well as therapy resistance. Apoptotic signaling is characterized by caspase activation and nuclear disintegration, which is accompanied by altered nuclear exchange mechanisms. During apoptosis active caspase-3 is transported into the nucleus by a specific but unidentified mechanism. We found that downregulation of ceramide synthase 6 (CerS6), which preferentially generates C16-ceramides, reduces apoptotic signaling downstream of caspase-3 by inhibiting nuclear translocation of the activated enzyme. This pilot study will further study the novel link between nuclear translocation of active caspase-3 and sphingolipid metabolism.

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