Project No. 2118
Diego Gomez-Nicola – University of Southampton
James McCarthy – Senior Research Associate, Astex pharmaceuticals
Harpreet Saini – Director, Astex Pharmaceuticals
The role of tissue-resident macrophages is critical for maintaining homeostasis and ensuring a correct engagement of the immune system during infection.
In recent years, we, and others, have highlighted the function of the colony stimulating factor 1 receptor (CSF1R) as critical for the maintenance of several macrophage populations, including microglia, the main brain’s resident myeloid cell. For example, we have demonstrated that targeting CSF1R is effective in controlling the number and activation of microglia in health and disease, opening avenues for clinical intervention. Additionally, CSF1R dependent modulation of these cells has emerged as a useful tool in order to understand their role in health and disease. These results suggest that the control of key mitogenic signalling could control macrophage phenotype, and we aim to explore this broadly. Here, we will characterise the different aspects and levels by which the modulation of key mitogenic pathways can control the function of key tissue-resident macrophages, in order to understand fundamental aspects of the biology of the immune system.
To address this aim, the student will tackle the following specific objectives:
- Characterise the role of key mitogenic pathways in the control of the phenotype of tissue-resident macrophages, including microglia
- Investigate how the inhibition of mitogenic pathways can modify tissue function, via an effect on tissue-resident macrophages
- Provide a comparative study of common vs specific transcriptional modules regulated by key mitogenic pathways in different populations of tissue-resident macrophages, in mouse and human
The student will address objectives 1 and 2 by performing in vivo experiments using validated tool compounds to inhibit the function of key mitogenic pathways, for example tyrosine kinase inhibitors of CSF1R. She/he will explore dose-dependent impact on the transcriptional profile of specific tissue-resident macrophages (i.e. microglia, Kupffer cells, lung and kidney macrophages), using single-cell RNA sequencing (scRNAseq). For this, we will use the 10x platform available in Southampton, receiving support from Astex for the bioinformatic data analysis. We will identify specific cell subpopulations (or subtypes) displaying specific vulnerability to inhibition, as well as the main cellular functions being regulated by the specific receptor. This approach will be complemented by analysis of macrophages subtype and phenotype by FACS and immunohistochemistry, as well as analysis of tissue-specific physiological readouts. In objective 3, we will integrate the cell-specific datasets, in order to identify tissue-cell-specific mechanisms vs conserved responses. We will also validate our studies by performing scRNAseq of macrophages isolated from human, in order to identify species-specific mechanisms, and phenotypes. The experimental plan will be developed in close interaction with Astex pharmaceuticals, a company used to dissecting transcriptomic changes to understand underlying biology, gleaned from decades working in the oncology field.
This project will provide a solid training platform for a PhD student, by tackling outstanding biological questions within an enriching academic-industrial collaboration. This will lead to valuable insights about the immune system, with direct translation into our understanding of the role of immune function and dysfunction.