Microenvironmental training in the maintenance and breakdown of intestinal homeostasis

Intestinal homeostasis is maintained by integrated crosstalk between the microbiota, the intestinal epithelial barrier, the underlying stroma, and the host immune system. Designed to confer tolerance of commensal microflora, whilst providing effective defence against harmful insult, complex regulatory mechanisms have evolved to uphold this immunological balance. Breakdown of these pathways precipitates dysregulated intestinal inflammation that is the hallmark of inflammatory bowel disease [1, 2]. It is increasingly evident that the microenvironment within which cellular and microbial ecosystems interact has a direct impact on the tissue immune status; extracellular matrix molecules orchestrate controlled inflammatory responses by dictating spatial positioning of cells, patterning soluble effector molecules, and directly signalling to cells [3, 4]. However, surprisingly little is known about the intestinal microenvironment, nor is it clear how this changes during dysregulated homeostasis, and the functional implications of these changes.

This project will systematically reconstruct the intestinal microenvironment in the healthy gut and during inflammatory bowel disease. In vivo metabolic labelling of stromal cell subsets during well-characterized models of bowel disease will provide the first unbiased, in situ transcriptional profile of normal intestinal tissue, and reveal changes associated with the breakdown of intestinal homeostasis. Bioinformatic analysis focused exclusively on core matrix and matrix-associated genes, including soluble factors and their receptors, will highlight biological/cellular processes likely to be impacted by transcriptomic changes. Conservation of genes or pathways implicated in the breakdown of homeostasis in these models will be cross-referenced to human datasets, andclinical metadata. Candidates relevant to human disease will be prioritized for functional validation. In parallel, we will examine the mechanisms by which immunomodulatory matrix molecules programme the phenotype of immune and stromal cells [5], comparing the ability of wild type proteins with polymorphic variants associated with inflammatory disease to imprint transcriptomic, epigenetic and metabolic memory resulting either in immune tolerance or hypersensitivity in intestinal cells.

TRAINING OPPORTUNITIES
The Kennedy Institute is a world-renowned research centre, located in the heart of the University of Oxford’s Old Road campus, housing basic and clinician scientists working on diverse aspects of immunology and inflammation. This project will combine state of the art cellular immunology and tissue biology; training will be provided in a range of immunological, bioinformatic, imaging and molecular biology techniques. The PhD programme includes a core curriculum of 20 lectures in the first term of year 1, students will attend weekly group meetings, and will be expected to attend seminars in the department and relevant seminars in the wider University. Students will present their work at national and international meetings.