| 研究実績の概要 |
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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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
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. Efforts are now underway to prepare a manuscript for publication reporting the main findings of the project.
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