Study of the role of integrins and proteoglycans in heart disease
Updated project summary:
Understanding the causes of heart disease, particularly heart failure, remains an important goal in heart research. We know that the heart can detect and responds to changes in stress, such as high blood pressure and diabetes, however which proteins are critical to these responses is poorly understood. We and others have identified that two families of receptors, the integrins and syndecans, are involved in mediating how cells respond to various stressors. We believe targeting select members of these receptor families may improve heart disease patient prognosis, however first we face the hurdles of understanding at a mechanistic level how these receptors act in the heart.
To simulate the effects of hypertension on the heart we shall subject mice to aortic banding procedure. This surgery is conducted on 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. Overall these animals are graded under the "moderate" harm severity level.
We have observed differences in Akt signaling and downstream components in female Syndecan-4 WT vs KO mice in basal situations, but not in male KO mice. The Akt signaling pathway has been heavily studied in hypertrophic and fibrotic growth in the heart in for example aortic-banded/pressure overload models. We suspect these changes are due to deviations in insulin/estrogen signaling and would therefore like to investigate these differences in WT and KO Syndecan-4 mice. To study the effects of insulin on Akt signaling in Syndecan-4 mice, we need to stabilize blood glucose levels within and across cohorts by a short fast. Mice will be fasted for up to four hours immediately prior to euthanasia. Additionally, the effect of ageing will be studies, as estrogen signaling alters with age.
Understanding the causes of heart disease, particularly heart failure, remains an important goal in heart research. We know that the heart can detect and responds to changes in stress, such as high blood pressure and diabetes, however which proteins are critical to these responses is poorly understood. We and others have identified that two families of receptors, the integrins and syndecans, are involved in mediating how cells respond to various stressors. We believe targeting select members of these receptor families may improve heart disease patient prognosis, however first we face the hurdles of understanding at a mechanistic level how these receptors act in the heart.
To simulate the effects of hypertension on the heart we shall subject mice to aortic banding procedure. This surgery is conducted on 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. Overall these animals are graded under the "moderate" harm severity level.
We have observed differences in Akt signaling and downstream components in female Syndecan-4 WT vs KO mice in basal situations, but not in male KO mice. The Akt signaling pathway has been heavily studied in hypertrophic and fibrotic growth in the heart in for example aortic-banded/pressure overload models. We suspect these changes are due to deviations in insulin/estrogen signaling and would therefore like to investigate these differences in WT and KO Syndecan-4 mice. To study the effects of insulin on Akt signaling in Syndecan-4 mice, we need to stabilize blood glucose levels within and across cohorts by a short fast. Mice will be fasted for up to four hours immediately prior to euthanasia. Additionally, the effect of ageing will be studies, as estrogen signaling alters with age.