| 研究課題/領域番号 |
19H03405
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| 研究機関 | 国立研究開発法人国立循環器病研究センター |
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研究代表者 |
Pearson James 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (30261390)
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| 研究分担者 |
土持 裕胤 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60379948)
曽野部 崇 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70548289)
杜 成坤 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (90590646)
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| 研究期間 (年度) |
2019-04-01 – 2023-03-31
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| キーワード | coronary vessels / diabetes / ageing / oxidative stress / vasodilators |
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| 研究実績の概要 |
Metabolome analyses of myocardium from senescence accelerated mice (SAMP8) and resistance mice (SAMR1) on a high fat diet (HFD, 56% fat) revealed that in SAMP8 mice glycolysis was inhibited and abnormal purine metabolism increased xanthine oxidase (XO) activation and ROS generation relative to SAMR1 mice. While antioxidant GSH was upregulated and L-arginine availability was maintained in the HFD SAMP8 mouse hearts we found that eNOS phosphorylation at Ser1177 was downregulated in SAMP8 and upregulated in SAMR1 on the HFD. Notably, this resulted in reduced coronary microvessel perfusion (microangiography), but not macrovessels in the HFD SAMP8 mice. Importantly, high intensity exercise training for 8wks restored microvessel perfusion in the HFD SAMP8 through an increased NO contribution.
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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
COVID-19 resulted in the initial cancellation of the final experiments (exercise protocol) to complete study 1 and restricted animal experimentation for several months. However, in the latter part of the year we were able to prepare more mice and secure SPring-8 beamtime to eventually complete study 1 and perform preliminary studies on a diet induced diabetic mouse model with transcriptome (RNAseq) and proteome profiling. This diabetic model was found to be characterised by mild cardiac and coronary dysfunction that we attribute to metabolic inflexibility and mitochondrial dysfunction associated with elevated ROS production. This non-genetic diabetic model will be used in experiments in 2021.
Final characterization of coronary dysfunction mechanisms this year is expected to result in a submission of the first manuscript from study 1.
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| 今後の研究の推進方策 |
Having now confirmed the phenotype of our novel diabetic mouse model has the hallmarks of metabolic dysregulation and coronary dysfunction we will utilize this mouse in Study 2 to examine the ROS sources and signaling pathways that contribute to accelerated vascular ageing associated with diabetes. In addition, the roles of specific cardiac cell types in accelerated ageing will be determined in in vitro cell studies in Study 3. Finally, an appropriate transgenic mouse model colony will be established this year to provide animals for the final Study 4.
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