Modeling ALS progression by applying neuroinformatics to a novel in vitro human 3D tri-culture model of the disease
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the motor neurons degenerate, leading to symptoms of muscle weakness and progressive paralysis, resulting in the death of patients from respiratory failure. The development of disease modifying therapies have been largely unsuccessful due to the poor understanding into the mechanisms of the disease and the weak translatability of pre-clinical models used to identify lead compounds. Recent advances in stem cell technology provide us with the ability to generate human induced pluripotent stem cells from the somatic cells of patients that can be differentiated into any cell type under the appropriate conditions.
Here, through a collaboration between the Dr. Durcan lab from the Neurodegenerative Disorders Research Group, and Dr. Iturria-Medina’s lab from the Neuroimaging and Neuroinformatics Research Group at The Neuro, we aim to better understand the non-cell autonomous component of disease progression at the cellular level. Our goal is to create a new human ALS model in a dish, and combine this with the use of computational analysis normally applied to clinical and imaging data from large cohorts of patients to model the development of neurological diseases. Glial cells, including astrocytes and microglia from ALS patients and controls, will be co-cultured with motor neurons from the same patients or controls in a 3D spheroid model. These ALS and control spheroids will be subjected to different assays at several time points in order to acquire longitudinal imaging, survival, and functional data. This data will be subsequently fed into a computational analysis pipeline with the goal of highlighting the effect of microglia-astrocyte interplay on motor neuron survival, as well as identifying patterns of disease progression associated with specific mutations implicated in ALS.
Thomas Durcan , Montreal Neurological Institute and Hospital, McGill University
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