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Vascular pathologies underline devastating diseases ranging from auto-immune vasculitis (1) to the recent COVID-19 pandemic (2). Neutrophils, as the most abundant immune cells, have been reported to intimately interact with the vascular system either via direct cell-cell contact or indirectly through release of inflammatory cytokines or cellular substances. Fully functional mature neutrophils patrol in the circulation and tissues to exert anti-microbial activity through several mechanisms including release of cytotoxic products, reactive oxygen species (ROS), neutrophil extracellular traps (NETs) and pore-forming molecules (3). These activities can cause vascular tissue damage if poorly controlled.
Inflammatory responses trigger the release of immature neutrophils into the circulation and tissues. Immature neutrophils with abnormal functions have been reported to be present in inflammatory lesions in different diseases. Our recent work on auto-immune vasculitis has shown that immature neutrophils can generate dysregulated ROS to cause vascular leakage and damage that may lead to systemic vascular pathology(4). We have also observed that immature neutrophils extravasated into the tissue surrounding the temporal arteries of patients with giant cell arteritis (GCA) (4). This project will extend our analysis of clinical biopsies from GCA to other systemic vasculitides.
To further investigate the cellular and molecular mechanisms of neutrophils in vasculitis, we also will adopt and modify the recently developed model system of human vascular organoids (5). The system is a revolutionary technological breakthrough enabling in-depth study of human vasculature in diseases that lack relevant substitutive animal models. Using this vascular organoid system we will (1) monitor the interactions of neutrophils at different maturation stages with the vessels, (2) examine the effect of neutrophil ROS and NET generation on vascular damage and (3) assess the effect of suppression of neutrophil ROS generation as a potential therapeutic intervention in GCA, as well as other vasculitides.
The outcome of this study is expected to contribute significantly to the establishment of vascular organoids as a model to dissect the fundamental cellular and molecular events of neutrophils in vasculitis. Knowledge obtained from the novel neutrophil-vascular organoids system will advance the development of new targets for therapeutic interventions to prevent detrimental vascular damage that is implicated in many diseases such as auto-immune vasculitis.
Vascular organoids, Neutrophils, Vasculitis, Vascular pathologies
TRAINING OPPORTUNITIES:
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 immunological tool kits (cell isolation, FACS, ELISA, primary cell culture) and imaging (immunofluorescence on tissue sections) approaches. This rare opportunity to develop vascular organoids will involve stem cell reprogramming and culture. The candidate can benefit from the hands-on experience with these techniques in the Udalova lab, and from access to clinical samples and expertise in their immune analysis in the Luqmani group. Primary human neutrophils and plasma will be prepared from blood samples of patients with well phenotyped forms of vasculitis recruited by Prof Luqmani’s research team. Confocol microscopy will be applied routinely to validate organoid structure and to image neutrophil-vasculature interaction and vascular damages. Multiplex assays such as the Luminex assay will be used for patient plasma profiling to identify key signaling molecules that modulate neutrophil-vasculature interaction. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including inflammation, genomics, 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 lab and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with both internal and external collaborators on organoids development.
Immunology; Vascular Biology; Stem Cell Biology; Molecular, Cell and Systems Biology.
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