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Immune Development in a Piglet Model of Environmental Enteric Dysfunction


About This PhD Project

Project Description

Summary
Environmental enteric dysfunction (EED) affects 200 million children in low- and middle-income countries and has extremely detrimental consequences for long-term health. It is defined by gastrointestinal inflammation, reduced intestinal barrier function, increased susceptibility to infection and reduced nutrient absorption resulting in malnutrition and stunted growth. There is little understanding of the cause, development or pathology of EED and no reliable interventions. However, poor nutrition and problems with immune development appear extremely important. This project will assess immune development during EED in a piglet model. In the long-term, the data generated may inform the design of new therapeutics.

Background
EED is complex and cyclic where each symptom can be a result of, or lead to other symptoms but the trigger is unknown (1). Importantly, 70% of the immune system is in the gut, which is the largest interface between the host and outside world (2). Mammals are born with limited immunity which develops via a precise and well-defined sequence of events, driven by contact with antigens (3). Inflammatory diseases are being increasingly traced back to permanent alterations to this pattern of neonatal immune development (4). This is why understanding the sustained change in immunity associated with early EED is extremely important in gaining further insight into its causes, pathologies, and implications in long-term health (5).

Pigs share many features of immunology, gastrointestinal physiology, metabolism, microbiology and diet with humans (6-8) and are therefore valuable models for humans (9). Many of the characteristic features of EED happen in piglets subjected to early, abrupt weaning (10). This causes intestinal inflammation, disruption of gut function with induced morphology similar to EED, and results in a growth-check and increased susceptibility to infections (11). Under normal conditions, the gut recovers within 2 weeks. However, it is hypothesised that recovery from abrupt weaning will be compromised by subsistence-type post-weaning diets and/or sub-clinical infection with the intestinal parasite Cryptosporidium, endemic in animals and humans in developing countries. It is further hypothesised that disrupted patterns of immune development linked to unusual microbiotas and metabolic phenotypes will occur.

Workplan
A phase I award from the Bill and Melinda Gates Foundation funded the animal trial which has been successfully completed along with metabolic profiling and microbiota analysis. The results are encouraging and data and samples will be made available to this PhD project. Animal model At weaning (3 weeks) sibling piglets underwent one of four treatments; 1) adequate diet (control), 2) adequate diet and Cryptosporidium (infection control), 3) subsistence diet – EED or 4) subsistence diet with Cryptosporidium – EED with infection. At 5 weeks, relevant tissues were collected and frozen.

Aims and objectives
The piglet model of EED will be used to:

- Measure intestinal morphology and the expression of Tight-Cell Junction-associated proteins linked to intestinal barrier permeability

- Compare patterns of influx of inflammatory and regulatory immune cells into the neonatal gut and establish the relevance of the model to human EED

- Investigate B-cell generation and plasma cell differentiation, and subsequent immunoglobulin and antibody synthesis in intestinal tissues.

- Assess antigen presentation using specific monoclonal antibodies to known pig immune cell types which correlate with human immune cells.

-Quantify immune cell-cell interactions in the intestine

- Identify links between the immune and metabolic systems, and intestinal microbiota using an integrated multivariate modelling approach.

Training
FNS is the largest academic unit of its kind in the UK and was ranked as the highest such department for research power in REF 2014 scoring a 3.24 point average, one of the highest within the sector. Our recently refurbished laboratories are exceptionally well equipped with all the necessary technologies required to carry out this research (700 MHz Mass Spectrometer with solid-state NMR capabilities, LC-MS and GC-MS, several flow cytometers, 4-colour fluorescence microscopes and a fully equipped molecular biology suit). We provide a stimulating and supportive environment which facilitates timely completion of PhDs; 100% of RC-funded students submit within 4 years. PhD students produce brief written progress reports every six months and submit a detailed, vivaed report after 1 year. We provide courses to develop organisational, presentational and publishing skills, and formal monthly group research/progress meetings. Additionally, we provide weekly compulsory departmental seminars by internal and guest speakers, and an appropriate mentor.


References

"1 Prendergast A, Kelly P. Enteropathies in the developing world: neglected effects on global health. Am J Trop Med Hyg. 2012; 86: 756-63.
2 Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clin Exp Immunol. 2008; 153: 3-6.
3 Bjorksten B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol. 2001; 108: 516-20.
4 Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010; 160: 1-9.
5 Owino V, Ahmed T, Freemark M, et al. Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health. Pediatrics. 2016; 138.
6 Meurens F, Summerfield A, Nauwynck H, Saif L, Gerdts V. The pig: a model for human infectious diseases. Trends in Microbiology. 2012; 20: 50-57.
7 Roura E, Koopmans SJ, Lalles JP, et al. Critical review evaluating the pig as a model for human nutritional physiology. Nutrition research reviews. 2016; 29: 60-90.
8 Stachowiak M, Szczerbal I, Switonski M. Genetics of Adiposity in Large Animal Models for Human Obesity-Studies on Pigs and Dogs. Progress in molecular biology and translational science. 2016; 140: 233-70.
9 Groenen MAM, Archibald AL, Uenishi H, et al. Analyses of pig genomes provide insight into porcine demography and evolution. Nature. 2012; 491: 393-98.
10 Berkeveld M, Langendijk P, van Beers-Schreurs HM, Koets AP, Taverne MA, Verheijden JH. Postweaning growth check in pigs is markedly reduced by intermittent suckling and extended lactation. J Anim Sci. 2007; 85: 258-66.

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