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Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury
Third-party funded project
Project title Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury
Principal Investigator(s) Osthoff, Michael
Co-Investigator(s) Trendelenburg, Marten
Walker, Ulrich A.
Orgül, Selim
Organisation / Research unit Departement Biomedizin / Clinical Immunology (Trendelenburg),
Bereich Medizinische Fächer (Klinik) / Infektiologie (Battegay M)
Project start 01.01.2015
Probable end 30.06.2016
Status Completed
Abstract

Mannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce.  This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG).

In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual.

In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future.

In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited.

This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings.

Keywords complement system, mannose-binding lectin, ischemia/reperfusion injury, hypoxia, glaucoma, systemic sclerosis, systemic lupus erythemathosus
Financed by Foundations and Associations
University of Basel
   

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28/03/2024