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Getting BADASS with the role of the renin angiotensin system in disease


Bristol Medical School

About the Project

Rationale:
The Renin Angiotensin System (RAS) is a multi-functional hormonal system involving several enzymes and metabolites that regulate several physiological processes. Dysfunction in RAS, involving specific bioactive metabolites is associated with different forms of cardiovascular, renal, pulmonary, and neurodegenerative diseases. Very recently its involvement in all of these diseases has been brought into sharper focus by the COVID19 pandemic, caused by the spread of the SARS-CoV2 virus that gains entry to the body by binding to ACE2, a key RAS enzyme, which aids its internalisation and triggers imbalance between what are detrimental and protective RAS metabolite-mediated signalling mechanisms that most likely are responsible for the eventual outcomes of people who develop COVID19 disease.

There is a significant need to have tools available for the accurate measurement of the activity of the RAS to inform how the RAS may be involved in the diseases it contributes to. With increased emphasis towards more person-centred medicinal approaches for the treatment of disease the ability to identify and stratify people into groups based on particular profiles of activities in certain pathways holds much potential as is the need to continue to refine the measurement of outcomes in clinical trials. Traditionally components of the RAS have been measured by a combination of immuno-based approaches that allow the measurement of proteins and/or peptides individually or in smaller multiplex formats or, where scope allows, involved the use of mass spectrometry approaches. Rapid, cost effective and sensitive quantification approaches are needed if there is ever to be a successful translation to clinical applications.

Aims & Objectives
This is an inter-disciplinary project involving collaboration between the Bristol Medical School and the School of Chemistry and is designed to investigate the potential use of the Barrel Array Diagnostics And SenSing (BADASS) platform and method as a novel alternative way to measure RAS metabolites. It will study whether BADASS can address some shortcomings in sensitivity and specificity caused by existing antibody-based approaches, and/or cost/accessibility issues related to other multiplex and mass-spectrometry approaches. The project would develop methods for the detection and measurement of a number of key RAS metabolites and in turn pilot the application of this method different biosamples that will be available (e.g. serum, urine, post-mortem brain homogenates). The establishment of such a protocol will then provide opportunities to apply the method in conjunction ongoing studies around the role of RAS in neurodegenerative disease and/or COVID19 where the hypotheses being tested are to what extent derangement of RAS function contributes to disease.

Methods
This project will be based on the emerging findings of a recent programme of work undertaken with the support of an ERC Advanced Grant ABEL (340764) and we will explore how the same principles and approaches might be applied and modified for the measurement of an initial list of RAS metabolites. The project will progress In turn, following the development and validation of the approach to possibly develop methods to interpret and model the levels of RAS activity holistically, based on data from individual RAS metabolites and predictions of the activities of intermediate enzymes. We may then test measurements of RAS metabolites in conjunction with the ongoing measurement of SARS-CoV-2 in available urine and blood samples and/or with other more traditional measures of RAS function in post-mortem brain homogenates from patients who had neurodegenerative disease that are part of an ongoing project. The latter may also include important validation studies as to the impact of post-mortem delay in tissue samples on the sensitivity and potential application of BADASS in certain applications.

References

Thomas, F. et al. De Novo-Designed alpha-Helical Barrels as Receptors for Small Molecules. ACS Synth Biol 7, 1808-1816 (2018).

Kehoe PG. The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment? J Alzheimers Dis. 2018;62(3):1443-66.

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