Projects / Programmes
MD-2 inhibition for treatment bacterial infection and chronic diseases
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B510 |
Biomedical sciences |
Infections |
| B500 |
Biomedical sciences |
Immunology, serology, transplantation |
bacterial infection, sepsis, atherosclerosis, lipids, air pollutants, oxidative stress, innate immunity, Toll-like receptors, MD-2, drug design
Researchers (13)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
20,997 |
Abstract
Innate immune response enables the human body to recognize and rapidly respond to bacterial infection. One of the most potent inducers of the innate immune system is endotoxin (lipopolysaccharide – LPS), which initiates cell activation by direct binding to the protein MD-2, which is associated to the extracellular domain of the Toll-like receptor 4 (TLR4). Activation of this complex leads to inflamatory response with release of proinflammatory cytokines and other mediators. Besides response to bacterial infection, TLR4 is also involved in chronic inflammatory diseases such as atherogenesis as well as in response to several airborne pollutants. We plan to investigate the role of MD-2 in those inflammatory processes, which is currently unknown. Our preliminary results show that MD-2 is essential for cell activation by model airborne contaminant residual oil fly ash (ROFA). We will test two hypotheses on the mechanism of MD-2/TLR4 activation by ROFA, either through the chemical modification of MD-2 or indirectly through the oxidation of cellular lipids. The latter mechanism could share common mediators with atherogenesis. Minimally oxidized LDL activates TLR4, with clear implications for atherogenesis. We will test binding of pure oxidized lipids, such as POVPC and PGPC to MD-2 and their effect on cellular activation or stimulatory/inhibitory effect in combination with LPS. Inhibition of binding of activators (LPS, oxLDL) to MD-2 has the potential to inhibit initiation of signaling and may lead to potential drugs against sepsis as well as against above mentioned inflammation. We have previously proposed a 3D model of MD-2, confirmed by experimental data. We will select synthetic compounds based on the structural model of MD-2 and LPS for in vitro MD-2 binding assays using spectroscopic and immunochemical techniques and as antagonists on cell-cultures. Additionally we propose to identify endogenous molecules, which are able to bind to MD-2 and may thus represent initiators of sterile inflammation.
