Unraveling the intersection of immune responses in gut and cardiovascular and health

Are you fascinated by the intricate workings of the immune system and its pivotal role in health and disease? Join our cutting-edge PhD project at the Kennedy Institute and delve into the dynamic interplay between immune responses, cardiovascular health, and inflammatory bowel diseases.

The immune system is crucial for maintaining health and supporting organ function. When homeostasis is disrupted by inflammation, infection, or disease, the tissue microenvironment undergoes dramatic changes, including the loss and/or activation of resident and peri-vascular macrophages and the influx of newly recruited monocytes, macrophages, and inflammatory mediators. The immune responses are tissue-specific, but immune-stromal cellular crosstalk and immune-physiological system interactions are emerging as key drivers of clinical associations and co-morbidity in humans.

The Powrie lab established the concept of bidirectional interactions of the gut microbiome and  the host mucosal immune system, and how their disruption is implicated in the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders characterized by relapsing and remitting episodes of inflammation in the intestine. They showed that immune-stromal and subtissular niche-dependent immune responses have a key role in health and disease. The Monaco laboratory investigates how the immune system contributes to vascular homeostasis and disease. She broke new ground with the discovey that perivascular macrophages have a protective role in atherogenesis that can be therapeutically harnessed. Recent studies have highlighted a clinical association between inflammatory bowel diseases (IBD) and cardiovascular diseases such as atherosclerosis. Despite this emerging link, the molecular mechanisms underlying this association have been relatively neglected, representing a promising area for new discoveries.

Macrophages have a key role in health and disease, by supporting organ function and immune responses to damage and disease. In homeostasis, ontogeny and organ-specific signals influence the phenotype and function of macrophages by activation of specific transcription factors. Disruption of homeostasis due to inflammation, infection or disease results in a drastically altered tissue micro-environment with the influx of newly recruited monocytes and macrophages and inflammatory substances. This project will focus on the role of macrophages in the host microbe dialogue across IBD and CVD. We have recently applied single cell technologies to the identification of homeostatic vascular macrophages and we developed genetically modified strains designed to evalutate the role of specific macrophage subsets in health and disease. The PhD Candidate will utilise disease relevant and combined models, human biobanks, combined with spatial transcriptomics and proteomics technologies to map the local interactions of immune and stromal cells and how they contribute to disease. Emerging candidate metabolic, immunological and microbial pathways will be validated via targeted and/or conditional deletion to study their impact on both cardiovascular and gut health, informing target selection for future therapeutics.

As a PhD candidate you will gain a detailed understanding of the shared cellular and molecular mechanisms that link cardiovascular and gut health. Identify key pathways and cell populations that drive disease processes in both systems. We expect to uncover novel regulatory networks and signaling pathways that are common to both atherosclerosis and inflammatory bowel diseases.

KEYWORDS

Cardiovascular

Gut Inflammation

Homeostasis

Immunity

TRAINING OPPORTUNITIES

The student will benefit from the availability of in-house state-of-the-art single cell technologies including state-of-the-art germ-free facility, advanced microscopy and tissue imaging, disease-relevant models of atherosclerosis and inflammatory bowel disease, human biobanks, single cell biology, tissue imaging, spatial methodologies including spatial transcriptomics and CyTOF Hyperion for tissue imaging in human and mouse tissues.

KEY PUBLICATIONS

Cainzos-Achirica M, Glassner K, Zawahir HS, et al. Inflammatory bowel disease and atherosclerotic cardiovascular disease: JACC Review Topic of the Week. J Am Coll Cardiol 2020;76:2895-2905

Gu, Y., Bartolomé-Casado, R., Xu, C. et al. Immune microniches shape intestinal T_regfunction. Nature 628, 854–862 (2024). https://doi.org/10.1038/s41586-024-07251-0

Dib, L., Koneva, L.A., Edsfeldt, A. et al. Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis, increasing the risk of cerebrovascular complications. Nat Cardiovasc Res 2, 656–672 (2023). https://doi.org/10.1038/s44161-023-00295-x

Engelen SE, Robinson AJB, Zurke YX, Monaco C. Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat Rev Cardiol. 2022 Jan 31:1-21. doi: 10.1038/s41569-021-00668-4. PMID: 35102320

Park I, Goddard ME, Cole JE, et al. C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis. Nat Commun. 2022 Jan 11;13(1):215. doi: 10.1038/s41467-021-27862-9. PMID: 35017526

CONTACT INFORMATION OF ALL SUPERVISORS

claudia.monaco@kennedy.ox.ac.uk

fiona.powrie@kennedy.ox.ac.uk

jennifer.cole@kennedy.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025. 

Applications should be made to the following programme using the specified course code. 

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1) 

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13^th January 2025.