Crosstalk of metabolic and epigenetic pathways in systemic sclerosis (SSc)

Concept

Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown cause, which leads to disability and may cause premature death. SSc is characterized by massive accumulation of extracellular matrix proteins (=fibrosis) in skin and internal organs with permanent loss of organ function.

Decreasing/reversing fibrosis in patients with SSc can improve the prognosis of this devastating disease. Targeting metabolic pathways could reduce the production of extracellular matrix proteins by fibroblasts in SSc. This represents a promising new treatment strategy in SSc.

Facts and figures

Project lead
B Burja
University Medical Centre Ljubljana
blaz.burja@gmail.com
FOREUM research grant: €150.00
2018 - 2021

Meet the team

B Burja
University Medical Centre Ljubljana
M Tomsic
University Medical Centre Ljubljana
K Lakota
University Medical Centre Ljubljana
O Distler
University of Zurich
M Frank-Bertoncelj
University of Zurich

Objectives

We aim at exploring the crosstalk between metabolic and epigenetic pathways in SSc fibroblasts to uncover new anti-fibrotic treatment strategies. We will explore dysregulation of metabolic pathways in SSc fibroblasts and determine, whether metabolic substrates, such as aKG and glutamine influence the epigenetic state and pro-fibrotic activities of SSc fibroblasts. Targeting metabolic pathways might reverse epigenetic alterations and halt fibrosis in SSc with direct implications for drug discovery in SSc.

Interim results

TGFβ-activated skin fibroblasts from healthy controls and SSc patients exhibit changes in key regulatory enzymes of energy metabolism and mitochondrial dysfunction (e.g. HIF1alpha, PGC-1alpha). Observed dysregulations of TCA cycle metabolites could influence the activity of epigenetic enzymes (e.g. JMJD3) utilizing metabolic co-factors and lead to pro-fibrotic activation.

Metabolic perturbations caused by extrinsic addition of metabolite dimethyl-alpha ketoglutarate (aKG) and diethyl succinate affected the activity of the JMJD3-mediated H3K27me3, resulting in different expression of profibotic targets (e.g. collagen I, alpha-smooth muscle actin).