Project description
Tissue regeneration in multiple sclerosis
Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system (CNS) characterised by progressive destruction of neuronal tissue. Astrocytes, a subtype of glial cells, induce regenerative processes in acute inflammation but fail to inhibit tissue destruction in chronic disease. The EU-funded H I C I project will study the astrocytic heparin-binding EGF-like growth factor (HB-EGF) as a novel regenerative factor. The project's researchers previously discovered that HB-EGF acts as a tissue-protective factor in astrocytes, induced by the transcription factor aryl hydrocarbon receptor (AHR) in acute inflammation. However, HB-EGF decreases in chronic stages concomitantly with disease progression. In the current project, researchers will define the role of HB-EGF in acute and chronic autoimmune CNS inflammation and study mechanisms of its regulation by AHR.
Objective
Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS), in which chronic inflammation and failure of regenerative mechanisms lead to progressive tissue destruction and accumulation of neurological deficits. Glial cells such as astrocytes induce regenerative processes in acute inflammation, but fail to inhibit tissue destruction for yet unknown reasons in chronic disease. In preliminary studies, we identified heparin-binding EGF-like growth factor (HB-EGF) in astrocytes as novel tissue protective factor. Indeed, knock-down of HB-EGF in astrocytes led to exacerbated disease and failure to recover in an animal model of MS. Promoter studies revealed induction of HB-EGF by the ligand-induced transcription factor aryl hydrocarbon receptor (AHR) in acute inflammation. However, astrocytic HB-EGF decreased in chronic stages concomitantly with progressive disease worsening. Analyses of AHR binding sites in the HB-EGF promoter revealed epigenetic modifications mediated by DNA-Methyltransferase 1 (DNMT1) in chronic inflammation, which inhibited promoter activation by AHR. Knocking down DNMT1 prevented epigenetic changes and increased HB-EGF production in chronic stages. Thus, we have discovered astrocytic HB-EGF as a novel regenerative factor and its regulation by AHR and DNMT1, which could be targeted therapeutically to enhance tissue regeneration in chronic stages. In this project, we will define the role of HB-EGF in acute and chronic autoimmune CNS inflammation (Aim 1), its regulation by AHR and DNMT1 (Aim 2), and the therapeutic value of nasal HB-EGF application or DNMT1 blockade (Aim 3). In a translational approach, we will validate AHR ligands, HB-EGF and HB-EGF promoter methylation status in serum and cerebrospinal fluid of MS patients as novel biomarkers for MS (Aim 4). These high risk/high gain studies explore novel concepts for monitoring and therapy of yet untreatable stages of MS and other degenerative diseases of the CNS.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
91054 Erlangen
Germany