Investigating lipid metabolism and its impact on our immune system

RUSHWORTH_U23DTP1

During homeostasis the systemic immune response relies on the expansion and differentiation of blood stem cells.

In response to infection, these stem cells 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 infection the blood stem cells require energy to proliferate and differentiate into immune cells, however were this energy comes from is not fully understood.

To gain a better understanding of the mechanisms regulating the energy requirement for blood production during infectoin 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 metabolic requirement of haematopoiesis during infection. Specifically, we will determine the role of various lipid metabolites and regulators in these processes.

To do this, the 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 and metabolic methodologies including analysis of nucleic acids by qPCR and proteins by western blot, immunohistochemistry, Seahorse technology and metabolite uptake experiments. 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 their 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.

References
1. Mistry JJ, et al. Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection. Nat Commun. 2021 Dec 8;12(1):7130.

2. Moore JA, et al. LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation. J Clin Invest. 2022 Jan 6:e153157.

3. Mistry JJ, et al. ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24610-24619.

4. Shafat MS, et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. 2017 Mar 9;129(10):1320-1332