Descrizione del progetto
Rivelare il motivo per cui alcuni motoneuroni soccombono più rapidamente alle malattie rispetto ad altri
I motoneuroni alfa (aMN, alpha Motor Neurons), chiamati anche motoneuroni inferiori, sono i più grandi neuroni nel midollo spinale. Essi innervano i muscoli e li fanno contrarre. Un danno agli aMN provoca alterazione dei movimenti o paralisi ed è associato a una varietà di disturbi neuromuscolari, malattie e traumi. Esistono tre principali tipi di aMN a seconda del tipo di fibra muscolare che innervano: resistente alla fatica a contrazione lenta (SFR), resistente alla fatica a contrazione rapida (FFR) e poco resistente alla fatica a contrazione rapida (FF). Gli aMN FF sono particolarmente vulnerabili a molti stati patologici. MOVEMeNt sta approfondendo le differenze nei marcatori genetici tra i tre tipi per chiarire la vulnerabilità e la resistenza alle malattie. Lungo questo cammino, il progetto fornirà per la prima volta il trascrittoma completo per tutti e tre i tipi di aMN.
Obiettivo
Alpha motor neurons (aMN) are a clinically relevant neuronal population that selectively degenerates in neuromuscular diseases, including amyotrophic lateral sclerosis (ALS) and spinal bulbar muscular atrophy (SBMA). Distinct classes of aMNs (SFR, FFR and FF) degenerate at different rate in these diseases, with the fast fatigable (FF) MNs degenerating first. The molecular mechanisms underlying this selective vulnerability are only partially known. Understanding the molecular logics that shape the identity and function of aMN subtypes in vivo is directly relevant to the development of novel therapeutic strategies. Here I propose to harmonically integrate my solid background in dissecting the molecular fingerprints of distinct neuronal subtypes in adult mice by undertaking new technologies I pioneered at Harvard University, with new skills and knowledge I will build at the Host Institution, which will be critical for the successful achievement of my goal. The overreaching goal of MOVEMeNt is to identify the molecular substrate of disease vulnerability in aMNs. I will (Aim 1) isolate and FACS-purify aMN-nuclei from adult mouse spinal cords, based on the specific expression of aMN markers. Single cell transcriptomic analysis will reveal class-specific molecular fingerprints, including factors playing key roles in suptype-specific development, function, and disease vulnerability. I will also (Aim2) analyze the transcriptional changes of differentially vulnerable aMN classes upon retrograde labeling and functional denervation by neurotoxin intoxication. This work will return candidate genes directly controlling terminal sprouting and remodeling, critical steps that disease-resistant aMN subtypes normally undertake for neuronal loss compensation upon insult. More broadly, I aim to contribute in filling an important knowledge gap by generating the first transcriptomic roadmap of aMN subtypes, and pinpointing at new candidates for therapy development.
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
35122 Padova
Italia