2020 Fiscal Year Research-status Report
Drug screening system for early pathology of SBMA using disease specific iPSCs and novel biomarkers
| Project/Area Number |
20K16587
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| Research Institution | Aichi Medical University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Keywords | Motor Neurons / SBMA / Neurodegeneration / iPSC |
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| Outline of Annual Research Achievements |
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset slowly progressive motor neuron (MN) disease caused by mutations in the Androgen Receptor (AR) affecting its normal functioning through pathways yet unknown. Current treatments for SBMA target only its symptoms, and animal models developed thus far have been lacking, creating a need for the development of more appropriate human models. Induced Pluripotent Stem Cells (iPSCs) have in recent years become a valuable tool for developing human models of several diseases, and our group has established SBMA disease specific iPSCs and generated an early-disease model using iPSC-derived MNs. Given that SBMA occurs at a later stage in life, recapitulating pathology using iPSC-derived MNs requires long-term culture and phenotypes are relatively mild, making further studies on the molecular causes of the disease difficult. In this project we have determined that optimizing culture conditions through the addition of stressors induces a marked early onset of pathology specifically in SBMA MNs, facilitating comparisons and allowing a clearer observation of phenotypes. Furthermore, this optimization allows us to better understand the molecular causes of the disease and helps open potential new avenues for treatment of SBMA in the future.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Replicating the pathology of SBMA in cells requires tracking of parameters for a relatively long time in order to observe pathological changes. Culture conditions for motor neurons are specifically tailored to promote and enhance neuronal survival, creating an environment where even diseased neurons grow and thrive, making comparisons between healthy and diseased neurons difficult to observe and evaluate. As a means of clarifying the differences between healthy and SBMA neurons in culture we first needed to optimize culture conditions and identify factors that could be masking the onset and progression of disease. At the current stage we have succeeded in isolating variables and establishing an optimized culture protocol to more clearly observe SBMA pathology in iPSC-derived motor neurons.
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| Strategy for Future Research Activity |
Further experiments will be carried out to better clarify the role of stressors on the onset and progression of SBMA, as well as further optimizing the culture conditions in order to establish a system that could be used to screen compounds that aim at treating or preventing neurodegeneration in SBMA.
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