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Mechanisms of toxicity of homocysteine and its derivatives in humans, mice and yeasts

Quantitative proteomics in the yeast hyperhomocysteinemia model

Project financed by National Science Center (UMO-2014/15/B/NZ2/01079), duration 2015-2019. Principal investigator: Dr Joanna Perła-Kaján.

The aim of the present project is to map and analyze N-homocysteinylation sites in the yeast Saccharomyces cerevisiae proteome. A hypothesis to be tested in this proposal is that N-homocysteinylation targets specific protein Lys residues thereby causing global changes in the cellular proteome under hyperhomocysteinemic conditions. We plan to map N-homocysteinylation sites in the yeast proteome and to compare yeast proteomes using stable isotope labeling by amino acid in cell culture. Successful completion of the present proposal will provide new, fundamental knowledge regarding protein N-homocysteinylation and identify metabolic and regulatory pathways affected by hyperhomocysteinemia. The results of this project will shed light on mechanism(s) underlying toxicity of hyperhomocysteinemia in yeast and will have implications for Hcy-related pathologies in humans. Proteins most prone to N-homocysteinylation in vivo to be identified in the present study could serve as disease markers in humans. The methods developed in this project will facilitate the analysis of N-homocysteinylation sites in other organisms, including human.

Auto-immune response, fibrin clot lysis and cardiovascular outcomes

Project financed by National Science Center (UMO-2016/23/B/NZ5/00573), duration 2017-2020. Principal investigator: Prof. dr hab. Hieronim Jakubowski.

Recent studies from the PI’s group using samples from a large RCT with over 2,000 CVD patients show that HTL is a predictor of acute myocardial infarction, independent of established risk factors and plasma tHcy. We therefore hypothesize that HTL causes CVD by promoting thrombosis and an auto-immune response. To test this hypothesis we will built on our prior studies of the Western Norway B Vitamin Intervention Trial (WENBIT) cohort. Accordingly, we plan to measure fibrin clot lysis times and levels of antibodies against N-Hcy-proteins in plasma from CVD patients, as well as to evaluate fibrin clot lysis parameters and anti-N-Hcy-protein antibody titers as predictors of myocardial infarction and mortality. We believe that this study will generate new fundamental information regarding mechanistic link between HTL, clotting/lysis parameters, and anti-N-Hcy-protein antibody titers and will lead to new insights into the causes, prevention, and treatment of cardiovascular pathologies associated with HHcy.