Assessment of the expression and function of selected innate immunity receptors on endothelial cells as a basis for the development of new therapeutic strategies in the prevention and treatment of atherosclerosis

My research interests include the pathogenesis of atherosclerosis, I focus mainly on determining its molecular mechanisms. The main goal of my research is to develop effective preventive and therapeutic methods. My research to date has focused on assessing the impact of pro-atherogenic factors on dysfunction; vascular endothelium. They include assessments of the role of oxidative stress in activating the inflammatory process in endothelial cells by inducing the expression of adhesion molecules (ICAM, VCAM), chemotactic factors (MCP-1), and activation of mitogen-activated kinase signaling pathways (ERK, JNK, p38) and the nuclear factor - KB The aim of the research is to evaluate the expression and function of innate immunity receptors in the development of inflammation in endothelial cells. The research will be carried out using: - cell cultures - endothelial cells from umbilical veins (HUVEC), - atherosclerotic plaque preparations (N 40), material currently collected from patients from the carotid artery during elective open endarectomy - the research will be performed in cooperation with the Department of Otorhinolaryngology of the Faculty of Dental Medicine of the Medical University of Warsaw (consent of the bioethical committee KB / 92/2008) - we have the clinical characteristics of these patients.  The implementation of the research includes: - determination of the expression level of the following receptors: TLR 2, TLR 4, TLR 7, TLR 9, RAGE, as well as the H1MGB1 protein and nuclear factor - KB in umbilical vein endothelial cells (HUVEC) before and after stimulation with ligands of the tested receptors by cytometry flow cytometry - evaluation of the effect of inhibitors of individual receptors on ligand-stimulated expression of the KB nuclear factor, HMGB1 protein (flow cytometry) and expression of IL-6 in endothelial cells (Elisa test) - evaluation of the expression of TLR 2, TLR 4, TLR 7, TLR 9, RAGE receptors and proteins H1MGB1 and nuclear factor - KB in atherosclerotic plaque by immunohistochemistry. Available scientific data indicate an important role of innate immunity receptors, ie: toll-like receptors (TLR) and receptors for advanced glycation end products (RAGE) in the pathogenesis of atherosclerosis. Improper activation of these receptors causes disturbances in the body's homeostasis. The lack of signaling by these receptors exposes the body to pathogenic attack, while over-activation causes the uncontrolled release of many pro-inflammatory cytokines and chemokines, leading to the development of inflammation, which in turn intensifies the development of the atherosclerotic process. The main challenge for the future of successful targeted therapy in patients with atherosclerosis is to inhibit the inflammatory process associated with this disease without affecting the body's innate immunity. Therefore, it is important to understand the signal transduction pathways and the function of individual innate immunity receptors and the role of their selective inhibitors. This will control the immune response and block negative processes for the host. Currently, we have only selective data in this area and it is necessary to conduct research documenting the impact of inhibition of the activity of these receptors on the development of atherosclerosis. The planned research will provide important and missing information on the role of innate immunity receptors in the induction of inflammation in endothelial cells. The effect of selective inhibitors of these receptors will be documented, the effect of which will indicate the possibility of using these inhibitors in the treatment of inflammation, which will allow the control of the immune response and blocking inflammatory processes without affecting the organism's natural protective barrier. Assessment of the severity of inflammation by determining the expression of selected receptors in atherosclerotic plaque collected from patients from the carotid artery will provide new data on the role of these receptors in regulating inflammatory processes. The conducted research will be the basis for the development of new, effective therapeutic strategies in the prevention and treatment of atherosclerosis.