2016 Fiscal Year Annual Research Report
Development of a novel therapy for sickle cell disease by Nrf2 activation
| Project/Area Number |
16H06639
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| Research Institution | Tohoku University |
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Principal Investigator |
Keleku Nadine 東北大学, 医学系研究科, 産学官連携研究員 (40781761)
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| Project Period (FY) |
2016-08-26 – 2018-03-31
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| Keywords | sickle cell disease / Nrf2 / Specific activation / oxidative stress |
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| Outline of Annual Research Achievements |
During the year 2016, we performed experiments using SCD:Keap1 F/F Tie1 Cre and SCD: Keap1 F/F LysM Cre mice in which Nrf2 activation is limited to endothelial cells and myeloid cells including macrophages, respectively. We confirmed the amelioration of inflammation and organ damages in both SCD:Keap1 F/F Tie1 Cre and SCD: Keap1 F/F LysM Cre mice compared with control (SCD: Keap1 F/F) mice, while experiments regarding oxidative stress are partially done and still going. Results of RNA-sequencing, which were done in place of Microarray assay to investigate the mechanism underlying the role of Nrf2 in SCD, show that endothelial specific activation of Nrf2 upregulated large range of genes such genes of heme metabolism (Hmox-1), phase I and II detoxification enzymes, antioxidants and others in the SCD:Keap1 F/F Tie1 Cre mice. In addition, we also performed imaging mass and CE-MS spectometry to study heme distribution as well as glutathione activity. Heme distribution in SCD:Keap1 LysM Cre mice was significantly lower than that in SCD:Keap1 Tie1 Cre mice, suggesting that Nrf2 activation in macrophages promotes heme degradation. To reproduce the results for SCD:Keap1 LysM Cre mice, further experiments are ongoing.
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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
We have successfully completed the analysis with SCD: Keap1 F/F Tie1 Cre mice. The experiments using mice with specific activation of Nrf2 in macrophages are ongoing. These delays are due to few numbers of animals obtained from breeding. As we finished the analysis with SCD: Keap1 F/F Tie1 Cre mice, we will dedicate the breeding space to SCD:Keap1 LysM Cre mice.
The study in DRC of Congo was delay for reasons related to the delay in the acquiring of necessary approval documents. As these documents are being processed right now, we expect the study to be speed up as soon as possible.
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| Strategy for Future Research Activity |
TThe 2017 research plan will be about:
I. Contribution of Nrf2 activation in macrophages to explain improvement of SCD
We will continue searching for major target genes of Nrf2 responsible for amelioration of SCD symptoms and analyzed the oxidative pattern in organs of SCD: Keap1 LysM Cre mice.
II. Submission of the paper for publication
III. Correlation between NRF2 expression and clinical history of human SCD patients in Congo. We are studying the correlation between NRF2 SNP (NRF2 expression levels) and clinical symptoms of SCD. We are going to collect SCD patients saliva for SNIP analysis and conduct informatics analysis using demographic data as well as clinical data (medication, pathological events). All these information, will determine the NRF2 contribution to improvement of SCD symptoms.
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[Journal Article] Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation.2017
Author(s)
Tsuchida K, Tsujita T, Hayashi M, Ojima A, Keleku-Lukwete N, Katsuoka F, Otsuki A, Kikuchi H, Oshima Y, Suzuki M, Yamamoto M.
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Journal Title
Free Radic Biol Med
Volume: 103
Pages: 236-247
DOI
Peer Reviewed
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