Molecular regulation of neutrophil development in inflammation
- Project No: NCKIR3
- Intake: 2022 KIR Non Clinical
Supervisor: Prof Irina Udalova
Co-Supervisor: Prof Mark Coles, Dr Abhinandan Devaprasad
Neutrophils are important effector cells of the innate immune system and are produced in large numbers in the bone marrow (BM) through stepwise differentiation of myeloid progenitors, featuring distinct morphological changes and stage-specific expression pattern of surface receptors (1). Upon entering into circulation, they patrol blood vessels and tissues for microbial and sterile challenges. Our earlier work confirmed that neutrophils play a central role in the initiation and perpetuation of aberrant immune responses and organ damage and that modulation of their numbers and functions leads to significant improvement in the pathogenesis of inflammatory arthritis and other forms of acute inflammation. Neutrophil populations are, however, not homogeneous. Many studies, including our own, described the presence of functionally distinct immature neutrophils into circulation during inflammation (2). The cell-intrinsic molecular regulators orchestrating the neutrophil adaptations in phenotype and function remain largely unexplored.
Our recent seminal work revealed transcriptional circuits that control neutrophil function and identified novel putative regulators. We showed active chromatin remodelling at two transition stages: bone marrow-to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil development and inflammatory responses. We have validated their function in newly generated mouse models with neutrophil-specific knockouts (3). The goal of this project is to generate the regulatory blueprint of neutrophil states in a signal-driven microenvironment based on the already identified and functionally validated novel neutrophil regulators. This will be done by using a combination of advanced genomic, epigenomic, immunological techniques, including cutting edge single cell technologies. The mechanistic multi-scale computationalmodels will be used to provide a knowledge constrained framework for quantitative analysis and interpretation of resulting experimental data (4). The new mouse models will be generated and used during the DPhil project to validate the role of the identified key regulators in various neutrophil-driven inflammatory conditions in vivo. The outcome of this study is expected to progress fundamental biology of neutrophils, increase our understanding of neutrophil activated subsets in disease and aid the development of new targets for therapeutic interventions in inflammatory disorders (5).
Neutrophils, inflammation, transcriptional regulators, genomics/epigenomics
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Training will be provided in techniques in a wide range of functional genomics approaches (RNA-Seq, ATAC-Seq, ChIP-Seq), immunological (cell isolation, tissue culture, FACS), and imaging (immunofluorescence on tissue sections) approaches, as well as cutting edge single cell platforms (10x, CyTOF) and computational pipelines. Recently developed novel in vivo models of inflammatory diseases will be extensively used and new models will be generated. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. Students will attend weekly seminars within the department and those relevant in the wider University. Students will be expected to present data regularly to the department, the Genomics of Inflammation group and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with members of the Rheumatoid Arthritis Pathogenesis Centre of Excellence (Glasgow/Birmingham/Newcastle/Oxford) as well as Novonordisk Immunometabolism consortium (Oxford/Karolinska Institute/University of Copenhagen).
- Ai Z, Udalova IA. Transcriptional Regulation of Neutrophil Differentiation and Function During Inflammation. Journal of Leukocyte Biology 2020 Mar;107(3):419-430.
- Wang L, Ai Z, Khoyratty T, Zec K, Eames HL, van Grinsven E, Hudak A, Morris S, Ahern D, Monaco C, Eruslanov EB, Luqmani R, Udalova IA. ROS producing immature neutrophils are linked to GCA vascular pathologies. Journal of Clinical Investigations Insight. 2020 Oct 15;5(20):e139163
- Khoyratty T*, Ai Z*, Ballesteros I, Mathie S, Eames HL, Martín-Salamanca S, Wang L, Hemmings A, Willemsen N, von Werz V, Zehrer A, Walzog B, van Grinsven E, Hidalgo A, Udalova IA. Distinct transcription factor networks control neutrophil-driven inflammation. Nature Immunology, 2021, in press.
- Jansen JE, Gaffney EA, Wagg J, Coles MC. Combining Mathematical Models With Experimentation to Drive Novel Mechanistic Insights Into Macrophage Function. Frontiers in Immunology. 2019,10:1283
- Devaprasad A, Radstake TRDJ, Pandit A. Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies. Frontiers in Immunology. 2021 May 24;12:669400.
Immunology; Molecular, Cell and Systems Biology; Genes, Genetics, Epigenetics and Genomics
Prof Irina Udalova