Epigenetics of the lung-brain axis in Multiple Sclerosis: unravelling the impact of smoking on disease pathogenesis and progression

Multiple Sclerosis (MS), inflammatory disease of the central nervous system, is a leading cause of unpredictable lifelong disability in young adults, with a yet unexplained rise in incidence.

Despite the known association between smoking and MS, the underlying mechanisms are still elusive and specific clinical applications are lacking. We propose that epigenetic mechanisms mediate the processes underpinning the impact of smoking in MS.

We aim to develop innovative analytical and cutting-edge experimental strategies, taking advantage of the stable and reversible nature of epigenetic marks to:Aim 1.

Identify novel molecular mechanisms underlying the impact of smoking in MS by generating omics data in pathogenic immune cells of the lung-brain axis and in relation to the major HLA MS risk factor and brain degeneration using case-control cohorts.Aim 2.

Functionally investigate smoking-associated changes using epigenome-editing in advanced (e.g. iPSC-derived) cellular models and in MS-like animal model.Aim 3.

Establish smoking-associated epigenetic marks that can serve as sensitive and specific biomarkers for early diagnosis and prognosis.With this project, we will translate findings from unique clinical material into advanced functional systems and address biomarker potential.

We believe this unprecedented approach will provide in-depth mechanistic insights into the impact of smoking, considerably advancing the field of MS and potentially other diseases with similar etiologies.