Descrizione del progetto
Rigenerazione tissutale nella sclerosi multipla
La sclerosi multipla è una malattia infiammatoria autoimmune del sistema nervoso centrale (SNC) caratterizzata dalla progressiva distruzione di tessuto neuronale. Gli astrociti, un sottotipo delle cellule gliali, inducono processi rigenerativi nell’infiammazione acuta, ma non riescono a inibire la distruzione tissutale nella malattia cronica. Il progetto H I C I, finanziato dall’UE, studierà il fattore di crescita simile al fattore di crescita dell’epidermide che lega l’eparina nell’astrocita (HB-EGF, Heparin-Binding Epidermal Growth Factor) come nuovo fattore rigenerativo. I ricercatori del progetto hanno dapprima scoperto che l’HB-EGF agisce negli astrociti come fattore protettivo dei tessuti, indotto dal fattore di trascrizione recettore degli idrocarburi arilici (AHR, Aryl Hydrocarbon Receptor) nell’infiammazione acuta. Tuttavia, l’HB-EGF si riduce negli stadi cronici in concomitanza con la progressione della malattia. Nel progetto in corso, i ricercatori definiranno il ruolo dell’HB-EGF nell’infiammazione autoimmune dell’SNC acuta e cronica e studieranno i meccanismi della sua regolazione mediante l’AHR.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
91054 Erlangen
Germania