The Pathophysiological Factors Driving Diastolic Dysfunction of the Right Heart in Pulmonary Hypertension
| 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 2022)
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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 / Microtubules / Heat Shock Proteins / Cardiomyocyte |
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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 the first year of this proposal, I have begun developing the model of Group 2 pulmonary hypertension, using the Dahl-Iwai salt-sensitive (DIS) rat combined with a 4% NaCl diet for 12 weeks. So far we have established that when compared to the salt-resistant (DIR) control rats, DIS rats tend to develop left ventricular hypertrophy and demonstrate evidence of early diastolic dysfunction. Right ventricle (RV) catheterisation has revealed that DIS rats have slightly elevated pulmonary pressures, in particular during cardiac fluid challenge testing. Further analysis of RV diastolic function is function is currently being undertaken.
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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 rat model of Group 2 pulmonary hypertension is currently being fully validated, however the data collected to date is very promising. It is expected that full haemodynamic characterisation will be completed by summer 2023, followed by extensive cardiomyocyte function and biochemical studies.
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| Strategy for Future Research Activity |
As mentioned above, upon completion of the validation of the group 2 pulmonary hypertension model (planned summer 2023), cardiomyocyte function and biochemical studies will begin to investigate the roles of the extracellular matrix, microtubules, saromeres and organelles in the development of RV diastolic dysfunction. This is expected to make a majority of FY2023.
In early 2024, I plan to begin investigating if boosting small heat shock proteins within the myocardium may be a useful therapeutic strategy to alleviate diastolic dysfunction of the RV in both group 1 & group 2 pulmonary hypertension.
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Report
(1 results)
Research Products
(3 results)
