Metabolic Characterization of Natural Killer T Cell responses to sterile, hypoxic injury (360G-Wellcome-210842_Z_18_Z)


It has been described that ischemia-reperfusion injury (IRI), such as during organ transplantation, evokes damaging sterile inflammation and secondary tissue injury that is dependent on iNKT cell activation, but the underlying mechanisms remain elusive. Similarly, in sickle cell disease (SCD) mice, RBC sickling and widely disseminated microvascular ischemia can be triggered by hypoxia/reperfusion (H/R), presenting a global and scalable model of sterile, NKT-mediated inflammation. We propose here to use state-of-the-art metabolic methodologies to investigate the response to hypoxia and reperfusion (H/R), which ultimately causes NKT cell activation and tissue damage in SCD. Mice carrying the human sickle cell alleles are available and were crossed with NKT-deficient Ja18 mice, thus generating our novel Sickle-Ja18 mouse model which exhibits reduced tissue damage in response to H/R. Together with in-vitro co-culture experiments, we will explore (1) the intrinsic and (2) APC-mediated mechanisms of sterile inflammation caused by hypoxia and reperfusion in the context of sickle cell disease with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis. We anticipate that this research will increase our understanding not only of SCD, but also the pathology of IRI, organ transplantation and sterile inflammation.

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Grant Details

Amount Awarded 250000
Applicant Surname Riffelmacher
Approval Committee Basic Science Interview Committee
Award Date 2018-04-24T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 210842/Z/18/Z
Lead Applicant Mr Thomas Riffelmacher
Partnership Value 250000
Planned Dates: End Date 2022-05-01T00:00:00+00:00
Planned Dates: Start Date 2018-05-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Fiona Powrie