Immunometabolic regulation of stressed haematopoiesis: impact of ageing

RUSHWORTH_U21DTP1

During homeostasis the systemic immune response relies on the expansion and differentiation of haematopoietic stem cells (HSC).

In response to infection, HSC promote the rapid immune response by generating innate and adaptive immune cells that are recruited into the liver and the intestine to support the response to infection. During ageing, HSC self-renewal is lower and linage commitment is compromised, resulting in an overall defective immune response. Consequently, during the ageing process there is an increased incidence of myeloid-related malignancies and of a chronic low-grade systemic inflammation. Gaining a better understanding of the mechanisms regulating haematopoiesis during ageing will enable us to propose strategies to preserve and improve the systemic immune function and to overall maintain whole-body health. Therefore, the aim of this project is to define the mechanisms underpinning haematopoiesis during ageing and in response to declining liver function. Specifically, we will determine the role of various metabolic regulators in these processes.

To do this, the PhD student will learn in vivo techniques including animal handling, as well as isolation of primary cells for functional characterisation. The student will receive training in cellular biology methodologies including, analysis of nucleic acids by qPCR and proteins by western blot, ELISA and immunohistochemistry. The student will also learn to characterise the different HSC and immune cells compartments by FACS. This training will provide the student a series of valuable transferable skills essential for the progression of her/his scientific career.

The project will be carried out at the Rushworth Lab based at the Bob Champion Research and Education building, Norwich Medical School, the University of East Anglia, which combines research laboratories with medical training facilities. This work will be in close collaboration with the Beraza Lab at Quadram Institute Bioscience.

References:

ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection.Mistry JJ, Marlein CR, Moore JA, Hellmich C, Wojtowicz EE, Smith JGW, Macaulay I, Sun Y, Morfakis A, Patterson A, Horton RH, Divekar D, Morris CJ, Haestier A, Di Palma F, Beraza N, Bowles KM, Rushworth SA.Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24610-2461.

Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability. Isaacs-Ten A, Echeandia M, Moreno-Gonzalez M, Brion A, Goldson A, Philo M, Patterson AM, Parker A, Galduroz M, Baker D, Rushbrook SM, Hildebrand F, Beraza N. Hepatology. 2020 Mar 13.