Gene therapy with phosphodiesterases in heart failure
-We would like to investigate the effects of PDE4B, PDE3A and PDE2A gene expression on heart failure with preserved ejection fraction (HFpEF).
- The expression of PDEs is expected to improve the outcome of heart failure in the animals with HFpEF
- DSSLepR fat rats are expected to develop diastolic dysfunction, obesity and high blood pressure from age around 15 weeks and can eventually reach the human end point around the age 20 weeks.
- HFD + L-NAME-fed C57BL/6N mice are expected to develop alterations characteristic of HFpEF by 5-15 weeks after initiation of HFD + L-NAME feeding
-The gene expression that will be achieved after tail vein injection of AAV vector (replication defective recombinant adeno-associated virus vector) in rats or mice will allow inducing an optimal expression in the heart while limiting the expression in other organs and therefore reducing the unnecessary systemic effects. There is no medication or group of medications known until now to improve the survival of HFpEF. Therefore, the success of this therapeutic approach will be beneficial for the society.
-For the study, we will need 30 wistar rats, 30 DSSLepR lean rats and 126 DSSLepR fat rats. For mice, the numbers needed will be 346 (140 normal fed, 206 HFD + L-NAME fed)
-We will accomplish the requirement of 3R by:
Performing parts of our investigation in cells (cell lines and primary cells)
Performing some preliminary experiments to optimize the system and avoid repetitive experimentation
Performing many measurements in each animal whenever possible and accepted for the wellbeing of the animal. This will help to reduce the total number of animals for the study.
The animals will be kept in the required cages by the KPM personnel.
Based on the above points, we are seeking permission to conduct detailed studies including physiological in vivo experiments in rats and mice and ex vivo and in vitro experiments utilizing organs, tissues and cells from rats and mice.
- The expression of PDEs is expected to improve the outcome of heart failure in the animals with HFpEF
- DSSLepR fat rats are expected to develop diastolic dysfunction, obesity and high blood pressure from age around 15 weeks and can eventually reach the human end point around the age 20 weeks.
- HFD + L-NAME-fed C57BL/6N mice are expected to develop alterations characteristic of HFpEF by 5-15 weeks after initiation of HFD + L-NAME feeding
-The gene expression that will be achieved after tail vein injection of AAV vector (replication defective recombinant adeno-associated virus vector) in rats or mice will allow inducing an optimal expression in the heart while limiting the expression in other organs and therefore reducing the unnecessary systemic effects. There is no medication or group of medications known until now to improve the survival of HFpEF. Therefore, the success of this therapeutic approach will be beneficial for the society.
-For the study, we will need 30 wistar rats, 30 DSSLepR lean rats and 126 DSSLepR fat rats. For mice, the numbers needed will be 346 (140 normal fed, 206 HFD + L-NAME fed)
-We will accomplish the requirement of 3R by:
Performing parts of our investigation in cells (cell lines and primary cells)
Performing some preliminary experiments to optimize the system and avoid repetitive experimentation
Performing many measurements in each animal whenever possible and accepted for the wellbeing of the animal. This will help to reduce the total number of animals for the study.
The animals will be kept in the required cages by the KPM personnel.
Based on the above points, we are seeking permission to conduct detailed studies including physiological in vivo experiments in rats and mice and ex vivo and in vitro experiments utilizing organs, tissues and cells from rats and mice.