FAM26F protein: Innate regulator of Type 3 immune responses

Breakdown in the balance between tolerance to harmless commensal bacteria and protection against pathogens leads to intestinal inflammation and development of inflammatory bowel disease (IBD), which is the common name for ulcerative colitis (UC) and Crohn's disease (CD). IBD affects approximately 1 in every 250 people in the UK. Current treatments (surgery or immunosuppression/immunomodulation) are not always effective and may cause serious side effects. Thus, new therapies are needed, but rational development of such therapies requires new target identification and validation. Recent genome-wide association studies (GWAS) have linked several gene polymorphisms with UC. Amongst these is one in the regulatory region of a newly described gene called FAM26F (Family with sequence similarity 26, member F). FAM26F expression is increased in the mucosa of patients with active UC compared to healthy controls. FAM26F also predicts the outcome of corticosteroid therapy in rheumatoid arthritis (RA), the therapy that is also used to treat UC patients. To understand FAM26F function, we have generated FAM26F-deficient mice and found that FAM26F controls the induction of inflammatory cytokines, which are associated with UC disease progression, and instruction of T helper (Th17) T cell responses. We now seek support to elucidate the mechanism of FAM26F function and its clinical significance, using UC as a model. We have also identified FAM26F-deficient humans, which will allow us to directly translate findings made in mice to humans. Achieving these objectives will generate new therapeutic targets and/or biomarkers needed to better manage and treat UC or other Th17-linked diseases.

MFs and DCs are tissue resident cells of the innate immune system. Under homeostatic conditions, they promote tolerance but upon injury or infection they capture microbial antigens to induce a productive effector responses. To elicit productive effector responses, we recently reported that MFs and DCs integrate signals from different classes of membrane receptors (e.g. cytokine receptors and microbial-sensors) which report on the tissue state. To understand how the signal integration in MFs or DCs is translated into the adaptive effector responses, we discovered a poorly studied family of transmembrane proteins FAM26. One member of this family, FAM26F, has recently been linked in genome-wide association studies (GWAS) with ulcerative colitis (UC). We generated FAM26F-deficient mice and found that FAM26F is induced by bacterial and fungal stimuli on APCs, that it regulates induction of inflammatory cytokines associated with UC, and instruction of type 3 (Th17) T cell immune responses. Additionally, we have identified FAM26F-expression deficient humans, permitting direct translation of our results from mice to humans. We propose to use FAM26F-deficient mice and human blood samples to identify FAM26F function and interacting proteins in APCs (using proteomics and high resolution imaging approaches in Aim 1); to characterize mechanism by which FAM26F instructs Th17 responses (using RNASeq in Aim 2); and to understand the role of FAM26F in UC disease progression (using in vivo mouse UC disease models in Aim 3). We have established key collaborations locally, at University of Oxford (Prof. Kessler for proteomics, Prof. Dustin for imaging, Prof. Powrie and Dr. Jostins for biology of UC, Dr. Sansom for RNASeq), which will, with our own expertise in signalling, innate immunity and inflammation, ensure successful completion of the work proposed.

1. Who will benefit from this research?
In the short term, immediate beneficiaries of this research will be students and staff at the University of Oxford as this work will make up part of their professional training and career progression. Upon publication of our work beneficiaries will become other members of the scientific community (as described in Academic Beneficiaries section). Upon making our results available to the public though press releases, non-academic members of the wider public will benefit, as our research will enhance their understanding of inflammatory diseases in general, and UC in particular. In the long term, if FAM26F proves to be a good therapeutic target or a biomarker for UC, pharmaceutical companies and clinicians would benefit from the results of the proposed research.

2. How will they benefit from this research?
In the short term, staff working on this project will acquire new skills and knowledge (RNASEeq, proteomics, high resolution imaging, animal models of disease and work with human immune cells). These will form the basis for a future career in academic research, clinical career or career in pharmaceutical industry. Once published, our work will inform other researchers about the biology of a previously understudied family of proteins and will inspire further work in this area. For example, techniques used in this work such as high-resolution microscopy and single molecule photo bleaching, might inspire other immunologists and biochemists to apply them to other areas of signalling research. The knowledge generated about the mechanism underlying the function of FAM26F in innate cells will benefit neuroscientists studying other FAM26 proteins, such as FAM26C in the brain, or immunologists studying mechanisms underlying the innate instruction of adaptive immunity. To the public, our work will provide new insights into the biology of inflammatory diseases, which are one of the most widespread diseases of modern age. Specifically our research focuses on inflammatory bowel disease, and is of importance to the nation's health, as inflammatory bowel disease affects 1 in 250 people in UK, it is a life-long disease with significant emotional, health and financial burdens on the individual and the country. If our work uncovers FAM26F as a new biomarker or determinant of UC disease progression, it will provide critical knowledge needed for the rational design of the next generation of therapies and will be of interest to pharmaceutical companies and clinicians dealing with this disease.