Rewiring Metabolism to Restore Stress Adaptation in Darier Disease

Kathleen Green, PhD, Joseph L. Mayberry, Sr., Professor of Pathology and Toxicology Professor, Pathology (Experimental Pathology), Dermatology, has received funding from the LEO Foundation to study the underlying biology of Darier Disease (DD), which is a skin condition characterized by wart-like blemishes on the body.

Green shared the aims and the next steps of the project. 

Tell me about the grant you received. (The source, the $ amount, etc.): 

This is a three-year grant from the LEO Foundation, which is a Danish foundation that is one of the world's largest private funders of independent skin research, providing grants to support research that transforms the understanding of skin diseases. The budget requested approximately $585,752 over a three-year period. 

Is this a renewal or a new project?  

This is a new project, but this is our second grant from LEO Foundation.

What are the aims of the project?   

Arising from heterozygous variants of an endoplasmic reticulum (ER) calcium pump, SERCA2, Darier Disease (DD) belongs to a set of heritable acantholytic diseases for which the standard of care remains non-targeted topical steroids and retinoid treatment. Skin lesions resulting from loss of intercellular adhesion rarely appear pre-adolescence, suggesting that factors beyond heterozygosity contribute to disease pathogenesis. Our data show that DD cells are unusually sensitive to extrinsic oxidative stress, which we propose leads to a loss of function of the remaining good copy of SERCA2. The objective of the proposal is to force Darier’s cells into a state characterized by highly efficient production of the essential co-enzyme NADPH, to restore antioxidant defense that will help preserve cell adhesion and mitigate DNA damage.

What are your next steps?

Our next steps are to modulate enzymes that link glycolysis to a metabolic pathway known as the pentose phosphate pathway, which helps restore antioxidant activity in normal cells but appears to be deficient in DD cells.  We have identified a number of different enzymes to target, and will then assess the extent to which metabolism, cell adhesion and DNA damage response are restored.

What do you hope will come out of this funded research?

It is our vision that targeting DD metabolism to antioxidant defense not only stands as a novel therapeutic route for treating DD, it could also be more generally applied to other disorders linked to heterozygous genetic disease causing variants.

Learn more about this project.