Fibroseutvikling og hjertefunksjon i integrin a11-defekte og -overutrykkende mus, samt syndecan-4/a11 dobbel KO mus
The purpose of this study is to better understand the way the heart is able to detect changes when subjected to increased stresses, such as high blood pressure (hypertension). In such conditions the heart can change structurally, to the detriment of the patient, such that targeting the proteins involved in this process of remodeling may be therapeutic.
To simulate the effects of hypertension on the heart we shall subject mice to aortic banding procedure. This surgery is conducted on sedated and anesthetized mice, which reduces the distress the animals are subject to. Our surgeons are highly experienced at handling animals and mice recover very quickly from the surgery, with no signs of pain or distress when the animals awaken from the operation.
This work will lead to the development of novel therapeutic drugs, which target the proteins responsible for the development of heart failure, specifically diastolic dysfunction (DD). DD is forecast to become the most common cause of heart failure and today there are very limited therapeutic options for patients suffering from this ultimately fatal condition. Indeed patients diagnosed with heart failure have poorer prognosis than most cancers today. There is therefore a strong need to develop new effective therapies to target this condition.
We observe differences in Akt signaling and downstream components in female syndecan 4-/- compared to wild-type mice, which we suspect, is due to deviations in insulin signaling. To test our hypothesis, we plan to measure serum insulin and glucose levels. Considering the many gender differences in glucose metabolism and insulin sensitivity (Ahrén, 2000), we will compare adult (12-16 weeks old) syndecan-4-/- and syndecan-4 wild type, male and female mice. For fasting experiments, euthanasia will be performed as described in the original FOTS, by deep anesthesia and removal of the heart and the animals will not be subjected to any procedures before the fasting and euthanasia.
We shall use up to 2542 mice in this presented study. This number was determined from previous experience of the required animals to conduct the proposed experiments and the estimated survival of animals from the proposed surgical procedures. This figure also takes into account additional breeding required for back-crossing and maintaining colonies.
We actively apply the 3 Rs to this research proposal. Through improvements in surgical methodology we have reduced the mortality associated with aortic banding, so that we can reduce the number of required animals for this study. We continue to replace mouse studies with in vitro experiments, however limited replication of the complex 3D environment of the heart means many of the existing methodologies are insufficient for studying disease mechanisms and therefore animal models are still required for understanding the development of heart failure.
To simulate the effects of hypertension on the heart we shall subject mice to aortic banding procedure. This surgery is conducted on sedated and anesthetized mice, which reduces the distress the animals are subject to. Our surgeons are highly experienced at handling animals and mice recover very quickly from the surgery, with no signs of pain or distress when the animals awaken from the operation.
This work will lead to the development of novel therapeutic drugs, which target the proteins responsible for the development of heart failure, specifically diastolic dysfunction (DD). DD is forecast to become the most common cause of heart failure and today there are very limited therapeutic options for patients suffering from this ultimately fatal condition. Indeed patients diagnosed with heart failure have poorer prognosis than most cancers today. There is therefore a strong need to develop new effective therapies to target this condition.
We observe differences in Akt signaling and downstream components in female syndecan 4-/- compared to wild-type mice, which we suspect, is due to deviations in insulin signaling. To test our hypothesis, we plan to measure serum insulin and glucose levels. Considering the many gender differences in glucose metabolism and insulin sensitivity (Ahrén, 2000), we will compare adult (12-16 weeks old) syndecan-4-/- and syndecan-4 wild type, male and female mice. For fasting experiments, euthanasia will be performed as described in the original FOTS, by deep anesthesia and removal of the heart and the animals will not be subjected to any procedures before the fasting and euthanasia.
We shall use up to 2542 mice in this presented study. This number was determined from previous experience of the required animals to conduct the proposed experiments and the estimated survival of animals from the proposed surgical procedures. This figure also takes into account additional breeding required for back-crossing and maintaining colonies.
We actively apply the 3 Rs to this research proposal. Through improvements in surgical methodology we have reduced the mortality associated with aortic banding, so that we can reduce the number of required animals for this study. We continue to replace mouse studies with in vitro experiments, however limited replication of the complex 3D environment of the heart means many of the existing methodologies are insufficient for studying disease mechanisms and therefore animal models are still required for understanding the development of heart failure.