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H I C I SIGNED

Transcriptional and epigenetic control of tissue regenerative HB-EGF in autoimmune CNS inflammation

Total Cost €

EC-Contrib. €

Partnership

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H I C I project word cloud

Explore the words cloud of the H I C I project. It provides you a very rough idea of what is the project "H I C I" about.

modifications astrocytic multiple inflammatory revealed exacerbated ms decreased regenerative nervous cerebrospinal induce ligand acute transcription translational led fail neurological preliminary diseases model binding status protective egf inflammation sclerosis methyltransferase cells dna monitoring untreatable methylation central validate mediated gain serum destruction worsening knocking concomitantly accumulation dnmt1 stages induction recover chronic animal disease degenerative ligands regeneration epigenetic regulation cns risk inhibit astrocytes discovered mechanisms patients glial fluid therapy aryl biomarkers nasal knock promoter progressive deficits therapeutically tissue autoimmune sites therapeutic receptor unknown hydrocarbon explore heparin blockade hb inhibited activation ahr prevented

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 address: ISMANINGER STRASSE 22 city: MUENCHEN postcode: 81675 website: http://www.med.tu.muenchen.de contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
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.

#	participants	country	role	EC contrib. [€]
1	KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN Organization address address: ISMANINGER STRASSE 22 city: MUENCHEN postcode: 81675 website: http://www.med.tu.muenchen.de contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	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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