Signal Transduction in Leukocytes and Endothelial Cells
: (Alternative Format Thesis)

Student thesis: Doctoral ThesisDoctor of Science (DSc)


This collection of published primary papers, reviews and commentaries spans over 30 years of research. Collectively, they describe a body of work that has used interdisciplinary pharmacological, biochemical, cellular, molecular and genetic approaches to better understand the signal transduction events in leukocytes and epithelial cells that contribute to either immune activation and inflammation, cancer, metaplasia and/or morphogenesis Ultimately, this has been with a view to the identification of new drug targets and developing new therapies primarily for inflammatory disease, but also for cancer and regenerative medicine.
The papers presented demonstrate how my laboratory initially explored how antigen receptors, chemokines and cytokines control activation of T lymphocytes, key cells in the adaptive immune system. The strategy was to rigorously interrogate T lymphocyte biology at the fundamental level of biochemical signal transduction, with particular focus on the nature and functional relevance of receptor-operated calcium mobilisation and phosphoinositide lipid metabolism in human lymphocytes and leukemic T cell lines.

Eventually, I became focussed on phosphoinositide 3-kinase (PI3K)-dependent signalling and associated functional events in leukocytes. My interests developed further to explore: (i) the role of PI3K in functional events downstream of inflammatory mediators in colonic epithelial cells and their relevance to colitis and Crohn’s disease; (ii) signaling mechanisms involved in Barrett’s Metaplasia, a pathogenic condition characterized by replacement of stratified squamous epithelium of the distal oesophagus by columnar epithelium; (iii) the role of PI3K in embryonic lung branching morphogenesis, a key developmental process for the formation of many epithelial organs and (iv) novel post-translational protein modifications such as glycation and methylation.

More recently it has become clear that activation state of the PI3K pathway is correlated to a poor prognosis particularly in breast cancer patients. Given that PI3K inhibitors have entered the clinic for cancer, prognostic novel quantitative fluorescent microscopy methodology has been developed that identifies cancers in which PI3K is activated. Such approaches could be used in personalised medicine to better identify patients who would benefit from PI3K inhibitor treatment.
Date of Award3 Feb 2021
Original languageEnglish
Awarding Institution
  • University of Bath

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