| Project/Area Number |
22K15368
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 48020:Physiology-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Waddingham Mark 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 (70822211)
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| Project Period (FY) |
2022-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2024: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | Pulmonary Hypertension / Right Ventricle / Myocardium / Diastolic Dysfunction / Sarcomere / Myofilaments / Heat Shock Proteins / Cardiomyocyte / Microtubules |
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| Outline of Research at the Start |
Pulmonary hypertension (PH) patients often succumb to the associated right ventricle (RV) failure, for which there are no effective therapies. In this project, I will investigate the mechanisms underlying the development of RV diastolic dysfunction in 2 models of PH along with a novel treatment strategy for RV diastolic dysfunction. This project will utilise a "whole heart-to-myofilament" approach with numerous experimental techniques. It is hoped that this project will help enhance our understanding of RV failure development and evaluate a novel and rapidly translatable therapy.
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| Outline of Annual Research Achievements |
In FY2023, I have expanded upon our previous in vivo findings and completed a full Group 2 pulmonary hypertension model study using the Dahl-Iwai salt-sensitive (DIS)/4% NaCl diet (as previously described) and included normal diet DIS/DIR rats as controls. Briefly, we have demonstrated that DIS rats exposed to a 4% NaCl diet for 12-weeks exhibit subtle RV systolic and diastolic dysfunction in the absence of overt pulmonary hypertension (PH). Although challenging, the biochemical analysis of myofilament proteins conducted thus far has revealed that changes in the phosphorylation status of key myofilament regulatory proteins cMyBP-C, cTnI and MLC-2 correlate with the changes in RV function in the DIS rats.
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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
The Group 2 pulmonary hypertension model study is completed along with the full hemodynamic analysis. The collation and full interpretation of the hemodynamic data is near completion. Biochemical, histological and cardiomyocyte function experiments are underway with most already showing promising results. Moreover, myocardial x-ray diffraction studies at SPring-8 Synchrotron should be undertaken in late 2024/early 2025.
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| Strategy for Future Research Activity |
1. For the Group 2 pulmonary hypertension study, it is anticipated that the final collation and interpretation of the hemodynamic data will be completed by summer 2024. The biochemical, histological and cardiomyocyte function experiments are underway, but due to complexity of these experiments I expect that these will take a majority of 2024 to complete.
2. Myocardial x-ray diffraction studies at SPring-8 Synchrotron are planned for late 2024 or early 2025.
3. For the Group 1 PH studies, I will begin studies to investigate if boosting small heat shock proteins within the myocardium may be a useful therapeutic strategy to alleviate RV diastolic dysfunction associated with pulmonary hypertension. These studies will begin in spring 2024.
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