ACF Queen Mary Therapeutics or Clinical Pharmacology
2019 NIHR Academic Clinical Fellowship in Priority Research Themes
HEE Local Office: North Central and East London
Medical School: Queen Mary University of London
Research Theme: Therapeutics or Clinical Pharmacology
Specialty Options: Cardiology or Clinical Pharmacology and Therapeutics or Gastroenterology
The primary aim of this programme is to identify new ways to treat patients with heart disease that are based upon influencing the way that our friendly bacteria (called our microbiome) work in our bodies. In North East and Central London, the area that Barts Health Trust serves, we have some of the most varied and highest rates of cardiovascular disease within some of the most diverse communities in the UK. Thus, with the support of our patients we have an opportunity to interrogate causes, mechanisms and identify novel microbiome-based treatments in a patient population that has relevance at an international level. Very recently there has been an explosion of interest in the 'host' (meaning human) microbiome and its role in causing disease. In particular, evidence implicates dietary constituents including red meat, fat and choline that are processed by gut bacteria to generate damaging metabolites that have been associated with incidence and severity of cardiovascular disease. Similarly, the deranged metabolic activity of gut bacteria has been linked with gastrointestinal (Crohns disease, irritable bowel disease) and diabetic disease as have oral bacteria with negative health effects such as periodontitis and cardiovascular disease. In addition, our own work has led research demonstrating beneficial health effects of bacteria in the mouth that use a substance called inorganic nitrate to survive, but that in doing this these bacteria generate products that have a positive effect upon upon the cardiovascular function of the host. The aim of this programme will be to investigate causes, mechanisms and potential novel targets for therapeutics based upon the microbiome.
We propose an integrative bioinformatics strategy for the project including phylogenetics and metagenomics to investigate bacterial genes of interest. As an example, the full range of nitrate reductase genes in available metagenome data will be assessed via analysis of the expanding number of reference bacterial genomes and shotgun metagenome data made available by the Human Microbiome Project. We will conduct metagenomic shotgun sequencing, identifying potential nitrate reductases using known nitrate reductase family motifs and profile based homology searching. This will be conducted in specific disease cohorts such as patients with heart failure and coronary artery disease and compared with healthy volunteers.
Our deeper phenotyping capabilities enable identification of robust associations with variations in both host and microbiome genomics. These capabilities in cardiovascular include blood pressure measurement within our European Centre for Hypertension Excellence (Lobo, Caulfield), vascular function testing at the William Harvey Clinical Research Facility (Ahluwalia), circulating cell phenotyping at the Medical School Flow Cytometry suite and Cardiac imaging (Barts Heart Centre). It is envisaged that the project will encompass correlation of microbiome structure with functional cardiovascular parameters.
The development of therapeutics based upon targeting of the host microbiome has great opportunity for innovation. This approach has been neglected in the past but with the advancement in technology enabling identification of microbiome structure through next generation sequencing and the development of broad metabolomics coupled with advanced bioinformatics, this has enabled interrogation of large datasets with linkage to function. The strong existing multi-disciplinary infrastructure together with access to the diverse population at Barts provide this programme with substantial opportunity for innovations in therapeutics.