Descrizione del progetto
Proteinemicrogliali e morbo di Alzheimer
Con l’invecchiamento della popolazione globale, aumenta la prevalenza delle malattie associate all’invecchiamento. Tra queste c’è la malattia di Alzheimer (AD, Alzheimer’s disease), una condizione neurodegenerativa debilitante incurabile che causa perdita di memoria e di cognizione. Recentemente, alcuni ricercatori hanno identificato una mutazione protettiva in un gene associato alla AD. Il gene codifica una proteina abbondante nella microglia, costituita da cellule che inghiottono e digeriscono i detriti cellulari e le cellule morte nel cervello e nel midollo spinale, svolgendo un ruolo importante nell’immunità. iMIND sta creando linee cellulari microgliali umane da cellule staminali sane e di derivazione AD. Queste saranno modificate per esprimere la mutazione. Gli studi potrebbero chiarire nuovi meccanismi molecolari dell’AD e indicare eventuali terapie.
Obiettivo
Alzheimer’s disease (AD) is an irreversible neurodegenerative condition affecting 50 million people worldwide. To date, no disease modifying therapy for AD is available. Neuroinflammation is emerging as an important component of the disease. A recent GWAS analysis identified a rare protective coding mutation (P522A) in the PLCG2 (Phospholipase C Gamma 2) gene that is associated with AD. Interestingly, the gene encodes a transmembrane signaling enzyme that is highly enriched in microglia. The major aim of the proposal revolves around the functional characterization of the P522A mutation in microglia. To that aim, using an array of biochemical, imaging, functional, and transcriptomic assays, we will investigate human microglia generated from control- and AD patient-derived induced pluripotent stem cells (iPSCs). iPSCs will be gene-edited to generate P522A mutated isogenic cell lines. The proposal aims at identifying novel therapeutic targets and, in line with the objectives of the H2020 Framework Programme, explores new grounds in the molecular underpinnings of AD. The use of cutting-edge and innovative approaches (CRISPR/Cas9 gene editing, iPSC reprogramming, RNA-Seq analysis, high-throughput screening, and subcellular calcium imaging) provides a novel experimental model that is closer to the pathological processes of the AD brain and bypasses the limitations and shortcomings of preclinical AD animal models.
Campo scientifico
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
66013 Chieti
Italia