Ultrasound Imaging System (FUJIFILM VisualSonics Vevo F2)
Lead Research Organisation:
University of Surrey
Department Name: Veterinary Medicine & Science
Abstract
We are looking for funding to purchase an ultrahigh frequency and resolution ultrasound imaging system. Securing the funds for such a system will benefit several research areas at the University of Surrey. It will allow us to get a complete picture of the cardiovascular system as our current equipment can only study very small blood vessels and large blood vessels without information on function and blood flow. Of not it will allow us to use the same techniques used in humans and thereby allow direct translation of findings to patients. With this proposal, we focus on two research projects on cardiovascular diseases.
The ultrasound imaging system will allow us to visualise the function of the heart and blood vessels. Under normal conditions, the human heart contracts approximately once every second to provide the body with the required amounts of oxygen and nutrients. The heart needs to be able to respond rapidly to environmental changes, but also to increased demand and/or disease conditions. These stressful changes affect the functions of compartments within cells, called mitochondria, that are responsible for several key cellular processes, including energy regulation, calcium, and life-and-death decisions. For these reasons, mitochondria rely on protective mechanisms to overcome these stresses, which involve the coordinated action of various key proteins and cellular processes. Previously, Dr Ioannis Smyrnias (IS) identified key players in cells (i.e. the ATF5 protein) that regulate a network of proteins in a process called the mitochondrial unfolded protein response (UPRmt) that protects the failing heart during adverse conditions. IS will use the ultrasound imaging system with a novel, genetically altered mouse model that deletes expression of the ATF5 protein to unravel new mechanisms that benefit these protective processes in heart failure and reveal molecular targets required for the development of novel therapeutics against cardiovascular diseases.
Moreover, Prof Christian Heiss will use the F2 imaging platform to study each step of the ageing process on the heart, aorta, neck arteries and leg arteries non-invasively in individual animals using ultrasound. This is important as ageing is a highly variable process that is different between each all animal and humans. To allow comparisons between animals and humans it is important to use the same methods and ultrasound is a standard technique used on humans in hospitals. He will also test the impact of a diet, that is similar to what humans eat in western countries and leads to diabetes development, on cardiovascular ageing and test how a polyphenol substance in fruits, vegetable, tea and red wine (epicatechin) affects cardiovascular ageing. Of note epicatechin was already shown in humans to prevent cardiovascular events such as heart attacks, but nobody knows how. Using tissue samples collected at the end of parallel studies, he will link the development of cardiovascular ageing with molecular mechanisms of cardiovascular ageing.
Ultimately, the outcomes of our work at UoS will advance our understanding of novel and fundamental aspects of cell biology and, importantly, relate this to pathological conditions. Therefore, this work will contribute to long and healthy living.
The ultrasound imaging system will allow us to visualise the function of the heart and blood vessels. Under normal conditions, the human heart contracts approximately once every second to provide the body with the required amounts of oxygen and nutrients. The heart needs to be able to respond rapidly to environmental changes, but also to increased demand and/or disease conditions. These stressful changes affect the functions of compartments within cells, called mitochondria, that are responsible for several key cellular processes, including energy regulation, calcium, and life-and-death decisions. For these reasons, mitochondria rely on protective mechanisms to overcome these stresses, which involve the coordinated action of various key proteins and cellular processes. Previously, Dr Ioannis Smyrnias (IS) identified key players in cells (i.e. the ATF5 protein) that regulate a network of proteins in a process called the mitochondrial unfolded protein response (UPRmt) that protects the failing heart during adverse conditions. IS will use the ultrasound imaging system with a novel, genetically altered mouse model that deletes expression of the ATF5 protein to unravel new mechanisms that benefit these protective processes in heart failure and reveal molecular targets required for the development of novel therapeutics against cardiovascular diseases.
Moreover, Prof Christian Heiss will use the F2 imaging platform to study each step of the ageing process on the heart, aorta, neck arteries and leg arteries non-invasively in individual animals using ultrasound. This is important as ageing is a highly variable process that is different between each all animal and humans. To allow comparisons between animals and humans it is important to use the same methods and ultrasound is a standard technique used on humans in hospitals. He will also test the impact of a diet, that is similar to what humans eat in western countries and leads to diabetes development, on cardiovascular ageing and test how a polyphenol substance in fruits, vegetable, tea and red wine (epicatechin) affects cardiovascular ageing. Of note epicatechin was already shown in humans to prevent cardiovascular events such as heart attacks, but nobody knows how. Using tissue samples collected at the end of parallel studies, he will link the development of cardiovascular ageing with molecular mechanisms of cardiovascular ageing.
Ultimately, the outcomes of our work at UoS will advance our understanding of novel and fundamental aspects of cell biology and, importantly, relate this to pathological conditions. Therefore, this work will contribute to long and healthy living.
Technical Summary
With this proposal, we are seeking funding to purchase an ultrasound imaging platform for our in vivo imaging needs in preclinical research projects. The ultrasound imaging system will be used in projects from different research areas. With this application, we focused on two main projects that will immediately benefit from having access to an ultrasound imaging system.
Ongoing projects in Dr Ioannis Smyrnias' (IS) lab are designed to identify novel molecular targets within the ATF5/UPRmt signalling cascade(s) from which next generation therapeutics against cardiovascular disease can be designed. IS recently published the first study that described the ATF5-mediated protective effects of the mitochondrial unfolded protein response (UPRmt) in the failing heart. To expand upon these findings and demonstrate the in vivo contributions of ATF5 in the cardioprotective effects of the UPRmt, IS developed a novel cardiac-specific ATF5-deficient mouse model (csATF5-/-). IS will use the ultrasound imaging system to determine the effects of cardiac ATF5 deletion on cardiovascular function at baseline, as well as in the infarcted heart following experimental myocardial infarction. Moreover, ultrasound-guided intracardiac injections of AAV9 vectors expressing ATF5-regulated genes identified from an ongoing high throughput screen will reveal novel pathways engaged within the ATF5/UPRmt axis to protect the failing heart.
Prof C Heiss' (CH) research focuses on healthy ageing and to develop interventions to prevent cardiovascular disease development. The overall purpose of the current project is to characterise in mice the process of longitudinal, temporal and spatial sequence of cardiovascular ageing in individual animals, test the impact of a standard diabetogenic Western diet and a candidate intervention ((-)-epicatechin) on it. Finally, using tissue samples from parallel animals he will link the macromechanistic phenotype with molecular mechanisms of cardiovascular ageing.
Ongoing projects in Dr Ioannis Smyrnias' (IS) lab are designed to identify novel molecular targets within the ATF5/UPRmt signalling cascade(s) from which next generation therapeutics against cardiovascular disease can be designed. IS recently published the first study that described the ATF5-mediated protective effects of the mitochondrial unfolded protein response (UPRmt) in the failing heart. To expand upon these findings and demonstrate the in vivo contributions of ATF5 in the cardioprotective effects of the UPRmt, IS developed a novel cardiac-specific ATF5-deficient mouse model (csATF5-/-). IS will use the ultrasound imaging system to determine the effects of cardiac ATF5 deletion on cardiovascular function at baseline, as well as in the infarcted heart following experimental myocardial infarction. Moreover, ultrasound-guided intracardiac injections of AAV9 vectors expressing ATF5-regulated genes identified from an ongoing high throughput screen will reveal novel pathways engaged within the ATF5/UPRmt axis to protect the failing heart.
Prof C Heiss' (CH) research focuses on healthy ageing and to develop interventions to prevent cardiovascular disease development. The overall purpose of the current project is to characterise in mice the process of longitudinal, temporal and spatial sequence of cardiovascular ageing in individual animals, test the impact of a standard diabetogenic Western diet and a candidate intervention ((-)-epicatechin) on it. Finally, using tissue samples from parallel animals he will link the macromechanistic phenotype with molecular mechanisms of cardiovascular ageing.
