Descripción del proyecto
Las proteínas microgliales y la enfermedad de Alzheimer
A medida que la población envejece, las enfermedades relacionadas con el envejecimiento incrementan su prevalencia. Entre ellas figura la incurable enfermedad de Alzheimer (EA), una patología neurodegenerativa debilitante que provoca pérdida de memoria y cognición. Recientemente, unos investigadores identificaron una mutación protectora en un gen relacionado con la EA. El gen codifica una proteína abundante en la microglía, células que fagocitan desechos celulares y células muertas del cerebro y la médula espinal, y que desempeñan un papel importante en la inmunidad. iMIND está creando líneas celulares microgliales a partir de células madre obtenidas de la EA y sanas. Estas se editarán con el fin de que expresen la mutación. Los estudios pueden aclarar nuevos mecanismos moleculares de la EA e indicar terapias.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
66013 Chieti
Italia