Funded project summary

Award amount: £62, 500

Principal Investigator: Dr Ke Ning 
Institution: University of Sheffield, Department of Neuroscience
Project title: Development and validation of a human brain microphysiological system derived from induced pluripotent stem cells in amyotrophic lateral sclerosis (ALS)

Project Summary: Amyotrophic Lateral Sclerosis (ALS) is a rare and progressive adult-onset neurodegenerative disorder characterized by the progressive death of nerve cells in the brain and spinal cord. The mechanism of this disease has yet to be fully understood. Based on recent research, the nerve cell losses are roughly attributed to genetic, cellular, immunological and environmental abnormalities or stimuli. There is a lack of mechanistic understanding of the processes related to ALS. Therefore, there is a critical need for better models for drug development and the study of the disease. In recent years, the 3D (three-dimensional) nerve cell culture, called brain organoid, generated from induced pluripotent stem cells (iPSCs) have been reported as a useful platform for the modelling of the development of neural system diseases. In collaboration with Professor Thomas Hartung at Johns Hopkins University (USA), we have developed a novel iPSCs-derived human 3D brain microphysiological system (BMPS, also call organoid), which is comprised of mature nerve and glial cells. The aims of this project are: a) to induce a functional BMPS which contains all nerve cell subtypes and could represent different developmental stages of the nerve system; b) to investigate what causes cell death in ALS; c) to investigate oxygen levels of BMPS using lifetime imaging microscopy; d) to compare a special cell culture system (QV-900) with normal 3D cell culture and reveal whether the QV-900 is a better model for 3D culture. Three pairs of ALS and healthy control iPSC lines will be used for the proposed studies. Organoid size, RNA foci (a feature of this ALS), DNA damage (a key mechanism of ALS pathology) and cell death will be detected. The expected outcome of the study will imply whether the 3D BMPS has clear phenotype (characteristics and features of ALS) and can be used for novel drug screening for ALS treatments.