FRRB Project 3444218 - Multiomics pRofiling of patient spEcific Models to predict druggable targets in severe neuromuscular rare diseases
The Coordinator of the project is Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. The Lead Principal Investigator of the project is Prof. Yvan Torrente.
|Tematic Area:||Neurology - Rare Diseases|
|Project Start Date:||January 1, 2023|
|Project End Date:||December 31, 2025|
|Project Partners:|| - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- Fondazione Istituto Nazionale di Genetica Molecolare - INGM
- Università degli Studi di Milano
- Consorzio Italbiotec - ITB
Neuromuscular diseases collectively affect 160 per 100,000 people worldwide and are generally characterized by motor impairment and muscular atrophy. Despite variety of etiologies, dysfunctionality of components of the neuromuscular junction (NMJ), comprising a single motor neuron and bundle of muscle fibers innervated through synapses, is typically present. Humanized animal models have been the gold standard for neuromuscular disease modeling, but they are hindered by lack of human disease variability. We assume that in neuromuscular diseases the genetic or clinical heterogeneity is reflected by NMJ dysfunctions. The major aim of our study is to elucidate the different epigenetic mediators and cellular subpopulations involved in the NMJ pathologies such as Duchenne muscular dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS). We propose deeper NMJ analysis from muscle patient’s biopsies and a standardized 3D biofabrication platform consisting of iPSC-derived 3D-NMJ as reliable predictive models of DMD and ALS severity and progression. Integration of clinical data with genomics, transcriptomics, and epigenomics profiles of 3D-NMJ will provide valuable insights in NMJ susceptibility related to muscle pathology. The project will support mechanistic understanding of degenerative contributors to NMJ and development of innovative strategies, that will improve care for DMD and ALS patients.