Ether-Lipid Metabolism in Myeloid Cells in Atherosclerosis – Thelma

Several studies have shown that ether-lipid (plasmalogen) levels are altered in patients with metabolic disorders and are associated with cardiovascular risk. Plasmalogens possess a fatty alcohol at the sn-1 position of glycerol that is linked by a vinyl-ether bond, which confers them unique properties. TMEM189 (plasmanylethanolamine desaturase 1 PEDS1) the enzyme responsible for the last step, e.g. formation of the vinyl bond has been identified only very recently.
Direct evidence for the involvement of ether-lipid metabolism in myeloid cells and macrophages in the atheromatous process remains to be provided. Preliminary data indicate that TMEM189 is a promising target to investigate in myeloid cells. In humans, genetic variation at the TMEM189 gene locus is strongly associated with the monocyte percentage of leukocytes. Available data from single cell mRNA analysis demonstrate that Tmem189 is preferentially expressed in two macrophage populations within the plaque: foamy macrophages and inflammatory macrophages, these two populations playing a key role in plaque progression.
This research project will therefore specifically target plasmalogen metabolism within myeloid cells and will seek to assess the impact of this modulation on myeloid cells and macrophage functions and on the development of atherosclerosis in a mice deficient for Tmem189 in the myeloid lineage. It will also include a translational component with cohorts of patients presenting advanced stages of carotid atherosclerosis.