📋 Tender Overview
Generation Of Position Specific Organoids To Study Human Neuromuscular System Development And Disease
Organoid Model To Study Human Neuromuscular System Development And Diseasesdysfunction In The Interaction Between The Nervous System And Muscles Results In Deadly Diseases Such As Spinal Muscular Atrophy (Sma) And Amyotrophic Lateral Sclerosis (Als). The Eu-Funded Gpsorganoids Project Will Study The Regulatory Mechanisms Involved In The Formation And Maintenance Of The Human Neuromuscular System, And Their Disruption In Diseases, Using 3D Human Neuromuscular Organoids (Nmos). Nmos Have Previously Been Developed, Where Two Distinct Tissues, The Spinal Cord And Skeletal Muscles, Are Formed In Parallel, Self-Organise And Interact To Form Functional Neuromuscular Junctions. The Model Will Be Utilised To Study Als And Sma, Including The Establishment Of A Drug Screening Platform.
Funded Under
Excellent Science - European Research Council (Erc)
Total Cost
€ 2 799 375,00
Eu Contribution
€ 2 799 375,00
Coordinated By
Max Delbrueck Centrum Fuer Molekulare Medizin In Der Helmholtz-Gemeinschaft (Mdc)
Germany
Start Date
1 January 2022
End Date
31 December 2026
Objective
Locomotion results from the interaction between muscles and the nervous system. Dysfunction of such cells results in deadly diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). These diseases often show regional selectivity but the underlying reasons remain obscure due to the lack of a suitable model system. In previous work of my laboratory, we established a 3D neuromuscular organoid (NMO) model that allows the simultaneous generation of spinal cord neurons and skeletal muscle cells from human pluripotent stem cells (hPSCs) through a bipotent neuromesodermal progenitor (NMP). NMPs, located in the posterior part of the embryo, are driving axial elongation and coordinated growth of the trunk neuromuscular system. We coaxed hPSC derived NMPs to develop into neuromuscular organoids that form functional neuromuscular junctions supported by the presence of terminal Schwann cells and central pattern generator-like circuits. Thus, we are in the unique position to study in an organoid model the regulatory mechanisms involved in the formation and maintenance of the human neuromuscular system, and the disruption of these mechanisms in diseases. We will (i) identify the molecular requirements for the Generation of Position Specific (GPS) organoids representing distinct spinal cord segments, (ii) use NMOs to model and study ALS and SMA including the establishment of a drug screening platform and (iii) assemble hPSC-derived cerebral organoids and NMOs to include in the model human corticospinal tracts. In the long term, the information gained will have important implications for understanding and eventually treating neuromuscular diseases.
