Role of miRNA and posttranslational modifications as modulators of the functionality of high-density lipoprotein (HDL) in chronic kidney disease

• Applicant: Professor Thimoteus Speer, Ph.D.
• Subject Area: Nephrology
• Term: from 2017 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 351483950

Chronic kidney disease (CKD) represents one of the strongest risk factor for the occurrence of vascular events. The underlying mechanisms have yet been poorly understood. However, it is known that endothelial dysfunction, impaired regeneration of vascular lesions as well as a proinflammatory microenvironment may promote vascular diseases in patients with impaired renal function. In our previous work, we were able to document that uremia transforms the lipoproteins HDL and LDL into noxious particles, which induce endothelial dysfunction. Moreover, we revealed a strong associated between the structural phenotype and the functionality of these lipoproteins. Besides quantitative and qualitative alterations of the protein composition, posttranslational proteins modifications of HDL might represent a crucial modulator of its functionality. Moreover, HDL serves as a carrier for miRNA and conveys them to a variety of distinct cells. However, the relevance of such an altered structure of HDL under specific disease conditions - particularly CKD - has to be determined.It is the aim of the present project to examine on how posttranslational protein modifications (part 1) as well as HDL-associated miRNA (part 2) modulate the effects of HDL on vascular regeneration and inflammatory cell activation. In a translational study design, HDL isolated from patients with different degrees of renal impairment as well as healthy subjects will be used.In part 1, we will analyze posttranslational modifications of HDL-associated proteins in patients with CKD. Using HDL from these patients, healthy subjects as well as ex vivo modified HDL, the effects of these HDL preparations on vascular regeneration will be studied. For this purpose, we will use distinct in vitro (proliferation, migration, angiogenesis) and in vivo assays (murine carotid injury model/matrigel plug assay). Moreover, we aim to determine on HDL contributes to a proinflammatory microenvironment by activating the innate immune system.In part 2, we will study differences in the profile of HDL-associated miRNA between patients with CKD and healthy subjects. We will then analyze on how specific HDL-associated miRNA interfere with the functional properties of endothelial cells and monocytes to regulate vascular regeneration and inflammatory cell activation.In summary, these studies should contribute to a better understanding of the physiological und pathophysiological processes promoting vascular disease in general and particularly in patients with CKD. Moreover, we aim to identify HDL-associated miRNA as well as posttranslational protein modifications of HDL as novel therapeutic targets and/or biomarkers.

• DFG Programme: Research Grants