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.
| Description | 1) Despite recent therapeutic advances, millions of patients worldwide are estimated to suffer from heart failure. In the UK, the associated 5-year mortality is currently reaching 50% and the total annual healthcare cost for cardiovascular diseases exceeds £9b. To improve on these numbers, we need to develop new treatments against cardiovascular diseases. We study the mechanisms via which we can improve and/or maintain mitochondrial functions in the failing heart. Mitochondria are key components of our heart cells that regulate several important processes, including metabolism and generation of energy. We study how an evolutionarily conserved, protective pathway called the mitochondrial unfolded protein response (UPRmt) is regulated by the ATF5 transcription factor to promote organelle and cell survival during mitochondrial stress/dysfunction. From prior studies, we know that activation of the UPRmt has beneficial outcomes in the regulation of several biological processes, as well as adaptation to pathological conditions, including cardiovascular diseases. Recently, we described the activation of the UPRmt by a pressure-overloaded murine and human heart and proposed that robust stimulation of the UPRmt may provide a beneficial intervention strategy to reduce cardiovascular diseases. However, the molecular mechanisms and signalling events underpinning the UPRmt in mammals are only starting to emerge and remain overall elusive. We created a novel mouse model where the ATF5 transcription factor is removed only in the heart to characterise the effects of cardiac-specific ATF5 deletion on cardiovascular structure and function both at baseline and in stressed mice. This is an ongoing study, but we have initial evidence using the Vevo F2 ultrasound imaging system, to show that deletion of ATF5 has no measurable effect on cardiac function and morphology. We are in the process of establishing the in vivo role of ATF5-regulated signalling in the cardioprotective effects of UPRmt activation. 2) As part of a collaboration within the University of Surrey, a project on immunotherapy for bladder cancer is using an engineered virus to stimulate the host immune response and study the effects of an engineered virus against tumour growth in bladder cancer. Initial experiments, some of which required the Vevo F2 equipment, established a tumour model in vivo; however since this model represents only one stage of bladder cancer (carcinoma) and exhibits aggressive behaviour, further testing in a more physiologically relevant model of bladder carcinogenesis is warranted. Using this initial pilot study, the group have applied to the MRC to setup a model of bladder carcinogenesis to induce high-grade, invasive tumours in the bladder, which will offer superior predictability of tumour progression with established protocols detailing tumour induction, progression, and the influence of factors such as age and sex in C57BL/6J mice. |
| Exploitation Route | - A novel, cardiac-specific ATF5-null mouse model will be used to demonstrate the in vivo role of the ATF5/UPRmt signalling axis in the pressure overloaded failing heart in vivo. Mitochondria are crucial for cardiac function as they regulate several key processes (ATP generation, metabolism, cell survival). Mitochondrial dysfunction is a central feature in heart failure by contributing to oxidative stress, energetic deficit, calcium dysregulation, and cardiomyocyte death and, thus, considered a promising area with therapeutic potential. Unravelling new mechanisms that benefit mitochondrial processes in heart failure will reveal molecular targets required for the development of novel therapeutics against diseases associated with mitochondrial dysfunction, including cardiovascular diseases. - Testing an oncolytic virus in an in vivo model of bladder cancer will provide valuable insights into its efficacy and potential clinical utility in bladder cancer treatment. |
| Sectors | Healthcare |
| Description | Understanding cellular adaptation to stress: How do the mitochondrial and integrated stress responses communicate to protect the stressed heart? |
| Amount | £268,095 (GBP) |
| Funding ID | PG/23/11428 |
| Organisation | British Heart Foundation (BHF) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 12/2023 |
| End | 01/2027 |
| Title | Minimal-Invasive Approach for Standardized Induction of Myocardial Infarction in Mice |
| Description | We learnt this technique from our collaborators in Heidelberg, Germany and brought it to Surrey because it has a direct impact on the number of animals used in myocardial infarction studies, as well as reduces their consequential pain or distress since it's a minimally-invasive technique. This technique replaced traditional surgery methods to induce MI in mice. Briefly: This is published protocol for a novel echocardiography-assisted technique for MI induction in mice. From the published manuscript: For optimal standardization, we first evaluate the left anterior descending artery by high frequency ultrasound. In B-mode imaging of anesthetized mice, the left anterior descending artery is scanned from basis to mid-papillary level. Additional Color-Doppler enables visualization of smaller branches. After attachment of a neutral electrode, a micromanipulator-controlled monopolar needle is inserted into the closed chest and navigated to the target segment. Once the needle is on the vessel (confirmed by loss of Doppler signal and hypokinesia apical of the target site), the coronary is coagulated with high frequency electricity using an electrosurgical unit. Coating of the needle with only the tip being not insulated ensures selective energy transmission and avoids coagulation effects in the trajectory. After removal of the needle, successful MI can be directly validated by absence of blood flow distal of occlusion, akinesia in the affected part of the left ventricle (LV), and typical ECG changes within seconds). |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2024 |
| Provided To Others? | No |
| Impact | - Fewer animals used in myocardial infarction studies in vivo, as we replaced traditional surgery methods that had a significant mortality rate with a minimally-invasive technique that involves ultrasound imaging-guided injections. - Mice experience less pain and stress. |
| Description | Mechanisms of Longitudinal Cardiovascular Ageing |
| Organisation | University of Surrey |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Our expertise using this ultrasound imaging equipment (Vevo F2) and its availability at Surrey allows for the longitudinal, and spatiotemporal sequence of cardiovascular ageing in mice (assess cardiac function, macro- and microvascular structure, physicomechanics and function in the aorta, carotids, and hindlimb). |
| Collaborator Contribution | Longitudinal, and spatiotemporal sequence of cardiovascular ageing in mice (assess cardiac function, macro- and microvascular structure, physicomechanics and function in the aorta, carotids, and hindlimb). |
| Impact | No outputs yet. |
| Start Year | 2024 |
| Description | Monitoring of bladder tumour growth in mice |
| Organisation | University of Surrey |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Availability of ultrasound imaging to monitor growth of tumours following experimental procedure. |
| Collaborator Contribution | Availability of ultrasound imaging to monitor growth of tumours following experimental procedure. |
| Impact | No outcomes yet |
| Start Year | 2023 |