2019 Fiscal Year Research-status Report
Exploring the novel role of mitochondrial dynamics in schizophrenia
| Project/Area Number |
19K08041
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| Research Institution | University of Fukui |
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Principal Investigator |
岩田 圭子 福井大学, 子どものこころの発達研究センター, 助教 (30415088)
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| Co-Investigator(Kenkyū-buntansha) |
松崎 秀夫 福井大学, 子どものこころの発達研究センター, 教授 (00334970)
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| Project Period (FY) |
2019-04-01 – 2024-03-31
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| Keywords | oligodendrocyte / mitochondria / schizophrenia |
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| Outline of Annual Research Achievements |
In this project, we wish to address the impact of changes in mitochondrial biogenesis on central nervous system (CNS) development (especially the oligodendrocyte differentiation) and animal behavior. Neurons and synapses have long been the dominant focus of neuroscience, informing theories on pathophysiology of psychiatric disorders. However, majority of cells in the brain are not neurons but glial cells. We are performing experiments to address how oligodendrocyte differentiation regulated by mitochondria impacts on the higher brain functions and pathophysiology of schizophrenia (SZ) following our research methodology and approach.
Here, we report new findings from the first year of the project as follows;
PGC-1 alpha, a transcriptional coactivator, is a key regulator of mitochondrial biogenesis. More than 8 variants of human PGC-1alpha have been reported so far. First, we identified the novel PGC-1alpha variant which was involved in oligodendrocyte differentiation using the human oligodendrocyte cell line. In addition, the variant was expressed in the human brain. Intriguingly, it also expressed in human tissues other than the brain. The results suggest that the novel variant has important roles not in oligodendrocyte differentiation but also in developments or functions of other tissues.
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
From preliminary results, it was predicted that known PGC-1alpha variant was involved in oligodendrocyte differentiation. However, novel PGC-1alpha variant was identified as a regulator of oligodendrocyte differentiation in the human cell line. Therefore, it is needed to identify the novel variant in the mouse brain before generating conditional mutant mice deficient for the variant. For this reason, generation of the conditional mutant mice is a little behind schedule.
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| Strategy for Future Research Activity |
As it is written in Current Status, it is needed to identify the novel variant in the mouse brain before generating conditional mutant mice deficient for the variant. Then, we will generate the conditional mutant mice deficient for the variant specific exon by CRISPR/Cas9 system. Using the mouse, we will elucidate the role of the novel PGC-1alpha variant on oligodendrocyte differentiation and behaviours in vivo following the original plan. In addition, we will elucidate regulatory mechanisms of the novel PGC-1alpha variant in oligodendrocyte differentiation by identifying transcriptional activators and downstream target genes of the variant.
It is planned that I visit the Lab of CR (Prof. Scorrano), University of Padua, Italy and conduct experiments, especially mitochondrial analyses using imaging systems which are available in his Lab, and discuss about the project twice a year. It must be noted that the decision whether to take a passage to Italy needs to be made after assessing COVID-19 situation.
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| Causes of Carryover |
As it is written in Current Status, it is needed to identify the novel variant in the mouse brain before generating conditional mutant mice deficient for the variant. Therefore, the amount to be used next fiscal year has been incurred. We have plan to use the amount to generate conditional mutant mice deficient for the variant.
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