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Respiratory and anaesthetic characterisation, animal well-being, and refinement of advanced cardiovascular research models in large animal


   Bristol Medical School


About the Project

Supervisors:

Vito Domenico Bruno (primary supervisor), Raimondo Ascione

Background

Millions of patients globally are still suffering with severe cardiovascular disease leading to death or debilitating complications such as myocardial infarction, heart failure, stroke, and limb amputation (1-2). Hence, new drugs, gene/stem cell-based therapies and medical devices are being developed. However, this requires the use of complex preclinical large animal models (pig/sheep) highly relevant to humans to ensure their feasibility/safety. Running these models is more complicated than undertaking similar interventions in the NHS to ensure effective anaesthesia, specialist monitoring, pain control and adherence to Home Office rules and 3Rs principles (3). The University Translational-Biomedical-Research-Centre/TBRC is leading on the establishment/characterisation of these models: 1.myocardial infarction(MI;>200), for testing of new drugs/cells/gene therapies(4); 2.carotid artery replacement surgery(CAR;>60) for development/testing of new vascular grafts(5-6); 3.cardiac surgery with heart-lung machine(CS;>60) for testing new cardiac devices(7). This work has generated a unique clinical/surgical database registries with data on anaesthesia, respiratory function(haemo-gas analysis), blood pressure, heart rate, temperature, saturation, anticoagulation(activated clotting times-ACTs), pain control, nutrition, infections, animal well-being/suffering. The veterinary anaesthetist plays a pivotal role in model refinement, adherence to standards/3Rs/animal well-being, providing a key contribution to data acquisition/quality, procedural success rate/survival and financial feasibility/sustainability.

Aims and objectives

To study the anaesthetic/respiratory/animal well-being in large animal models of MI, CAR and CS. Key goal: to identify clinical/functional or molecular signatures of respiratory dysfunction impacting on post-procedural recovery/animal well-being with a view to refine the models if necessary. Specific aims: 1.to study respiratory-specific clinical, mechanical ventilation and functional parameters on prospective data already collected from experimental procedures involving these 3 models to identify predictors of sub-optimal/prolonged postoperative intubation and recovery; 2.to undertake molecular evaluations on plasma/lung samples to identify signatures predisposing to sub-optimal/prolonged recovery; 3.to correlate clinical, ventilation, functional and molecular data with pain control and animal well-being.

Methodology

We will focus on clinical/mechanical ventilation, respiratory indices, haemo-gas analyses, any used drug, anticoagulation levels, blood and tissue-based molecular profiling of inflammation(IL-6, TNF-alpha) and lung/cardiac injury(RAGE/troponins) and their association with animal well-being, pain score, appetite, weight gain, social behaviour, recovery/intubation time, and suffering. Some of the models are more invasive or require longer anaesthetic time. Hence, we will also undertake comparative evaluations among the 3 models to ascertain how their different levels of invasiveness and intubation time may impact on these biochemical markers and postoperative animal well-being/suffering. For aims 1 & 3 we will use data collected from 40-50 procedures for each model; for aim 2 we will use samples from n=8 in each model. The student will lead on clinical/anaesthetic and molecular data collection, database validation, and comparative evaluations. Statistical guidance will be provided by VD Bruno. Lab supervision will be provided by Sarah Smith. All clinical research will be performed at the TBRC facility. Any additional lab-based research will be undertaken in the Ascione’s lab, at the Bristol Heart Institute, in our laboratories based on Research Floor Level 7 within the Bristol Royal Infirmary, University of Bristol. The student will also benefit from any relevant University educational courses.

Apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences.

Please contact for further details on how to apply.

Apply now!


References

1. World Health Organization (2011). p. 2–13;
2. Circulation. (2012) 125:620–37;
3. https://nc3rs.org.uk/who-we-are/3rs;
4. Sci Rep 11, 18322 (2021). https://doi.org/10.1038/s41598-021-97834-y;
5. Journal of tissue engineering 12, 2041731420987529;
6. Journal of Nanobiotechnology volume 20, Article number: 71 (2022);
7. Biomater. Sci., 2020, DOI: 10.1039/d0bm00412j.

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