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Defining the role of liver B-cells in Biliary Atresia pathogenesis


Project Description

This is a PhD studentship in liver immunology in a translational environment using tissues from children with biliary atresia (BA), to understand pathogenesis and reveal new targets for therapy. Our student will benefit from training in liver immunology, single cell analysis tools and research skills (e.g. statistics, scientific writing, personal efficiency, communication, information management) offered by the University of Birmingham.
B cells are currently targeted in clinical trials for adult biliary diseases. This work will define if pro-inflammatory and/or pro-resolution B cell subsets are functional in children with BA. If this hypothesis is true, B cells would be a valid therapeutic target.
Located at the Centre for Liver and Gastroenterology Research which is one of the biggest transplant centres in Europe, our student will be part of a multidisciplinary team of scientists and clinicians working together to understand liver disease pathology. Outcomes from this research will help us decide if targeting B cells in BA could be of benefit to patients, to delay liver damage. Our specific objectives are designed to answer:
1. What is the detailed, deep phenotype and distribution of B cells in infants with BA? We will investigate hilum and peripheral biopsies at diagnosis and at end-stage disease (explant), using the latest multi-modal approaches.
2. What is the function of liver B cell subsets in infants with BA? Pro-inflammatory B cells secrete cytokines, co-stimulate T cells and/or differentiate into antibody producing plasma cells. These functions were restricted to certain B cell subsets in our adult end-stage disease patients so we have a clear profile for comparison.
3. Are liver B cells clonally-related and somatically hypermutated? We will perform clonal analyses of B cell receptor sequences to address this question.

Person Specification

Applicants should have a strong background in Biomedical Science, and ideally a background in Immunology and/or bioinformatics. They should have a commitment to research in Immunology in a translational setting and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biomedical Sciences related subjects.

Applications should be directed to Dr Zania Stamataki (email ).
To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

This is a 3-year PhD position fully funded by a BCHRF award.

References

1. Hartley JL, Davenport M, & Kelly DA (2009) Biliary atresia. Lancet 374(9702):1704-1713.
2. Bessho K & Bezerra JA (2011) Biliary atresia: will blocking inflammation tame the disease? An., Rev. Med.62:171-
3. 185. Lund FE (2008) Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol 20(3):332-338.
4. Feldman AG et al, (2013) B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia. PLoS One 8(8):e73644.
5. Chung BK, et al. (2017) Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis. Journal of autoimmunity 77:45-54.
6. Shetty S, et al., Recruitment mechanisms of primary and malignant B cells to the human liver. Hepatology. 2012 Oct;56(4):1521-31.


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