Investigating the molecular regulation of protein translation elongation during the development of lymphocyte lineages, and T cell immune responses.
Primary Supervisor: Prof Alison M. Michie, School of Cancer Services
Second Supervisor: Dr Megan MacLeod, Shool of Infection and Immunity
Rotation Project:
B and T cell populations are the cornerstones of adaptive immune responses, ensuring that specific pathogens are cleared and prevent subsequent infections by forming immune memory. The molecular processes responsible for generating lymphocyte populations and initiating an immune response are tightly regulated at the level of cellular proliferation. The elongation stage of mRNA translation consumes almost all energy and amino acids used during protein synthesis, thus providing a link between energy sensing pathways, such as mTORC1, and translation elongation. The mTORC1-regulated kinase eEF2K, is responsible for negatively regulating the GTPase eukaryotic elongation factor 2 (eEF2) by phosphorylation at T56, which excludes eEF2 from the ribosome, thus suppressing translation elongation. Utilising mouse models that modulate the eEF2K/eEF2 signalling axis, we aim to determine the fundamental role of eEF2K/eEF2 during lymphocyte development and adaptive immune responses.
The rotation project will focus on identifying the role of eEF2K and eEF2 in normal B and T cell development. The student will use established in vitro models (co-cultures with OP9 or OP9-DL1) and flow cytometry to perform phenotypic and functional characterisations. As the project develops towards a PhD project, we will extend these studies into in vivo transplant assays to determine the impact of eEF2K and eEF2 modulation on lymphocyte development and immune responses to influenza virus. Additionally, we will define the molecular mechanisms surrounding translation elongation, analysing the translatome of maturing lymphocytes with ribosome profiling (Ribo-seq) to understand how codon biases change at different stages of development/immune response. In this way we will uncover fundamental information about the role of protein translation during lymphocyte maturation.