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  • Project No: KIRC5
  • Intake: 2022 KIR Clinical

Primary Supervisor:  Prof Irina Udalova 

Secondary Supervisors: Prof Raashid Luqmani,Dr Lihui Wang

PROJECT OVERVIEW

Vascular pathologies underline devastating diseases ranging from auto-immune vasculitis to the recent COVID-19 pandemic (1). 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 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. These activities can cause vascular tissue damage if poorly controlled. Inflammatory responses trigger the release of functionally distinct immature neutrophils into the circulation and tissues in different diseases, including severe COVID-19, where we, and others, identify the presence of neutrophil progenitors (2). 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 (3). Moreover, we have unraveled novel cell-intrinsic molecular regulators of neutrophil maturation and phenotype and function that may lead to multiple therapeutic strategies tailored to specific conditions (4).To further investigate the cellular and molecular mechanisms of neutrophils function on vasculature, we 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 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 new drugs under trials in inflammatory diseases and the inhibitors of the identified molecular regulators (4) for their effect on vasculature state. 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. 

KEYWORDS

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.

KEY PUBLICATIONS

  1. (Ponte C, Martins-Martinho J, Luqmani RA. Diagnosis of giant cell arteritis. Rheumatology (Oxford). 2020 May 1;59(Supplement_3):iii5-iii16.
  2. Oxford Covid-19 Immunology Consortium. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. 10.1101/2021.05.11.21256877.
  3. Wang L, Ai Z, Khoyratty T, Zec K, Eames HL, van Grinsven E, Hudak A, Morris S, Ahern D, Monaco C, Eruslanov EB, Luqmani RUdalova IA. ROS producing immature neutrophils are linked to GCA vascular pathologies. Journal of Clinical Investigations Insight. 2020 Oct 15;5(20):e139163
  4. 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.
  5. Wimmer RA, Leopoldi A, Aichinger M, Wick N, Hantusch B, Novatchkova M, Taubenschmid J, Hämmerle J, Esk C, Bagley JA, Lindenhofer D, Chen G, Boehm M, Agu CA, Yang F, Fu B,  Knoblich Zj, Kerjaschki D & Penninger JM.  Human blood vessel organoids as a model of diabetic vasculopathy Nature 2019 565: 505–510.

THEMES

Immunology; Vascular Biology; Stem Cell Biology; Molecular, Cell and Systems Biology.

CONTACT

Prof Irina Udalova

Email: irina.udalova@kennedy.ox.ac.uk