H I C I SIGNED
Transcriptional and epigenetic control of tissue regenerative HB-EGF in autoimmune CNS inflammation
Total Cost €
0EC-Contrib. €
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Project "H I C I" data sheet
The following table provides information about the project.
| Coordinator |
KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Organization address contact info |
| Coordinator Country | Germany [DE] |
| Total cost | 1˙499˙706 € |
| EC max contribution | 1˙499˙706 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2019-STG |
| Funding Scheme | ERC-STG |
| Starting year | 2020 |
| Duration (year-month-day) | from 2020-03-01 to 2025-02-28 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN | DE (MUENCHEN) | coordinator | 1˙499˙706.00 |
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Project 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.
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