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Mechanism of anti-inflammatory activity of a phospholipid-like drug

Objective

Tumor necrosis factor alfa (TNF alfa) is a key pro-inflammatory cytokine that is produced and released mainly by monocytes and macrophages in response to an infectious organism. Unregulated release of TNF alfa may lead to chronic inflammation in the form o f an auto-immune disease, such as rheumatoid arthritis and Crohn's disease. TNF alfa was also shown to be involved in the development of several other disease states such as sepsis, multiple sclerosis, atherosclerosis, ischemic stroke, inflammation-linked cancer, and diabetes. Several inflammatory diseases are successfully treated by TNF alfa blockers, which are protein drugs and thus suffer from several major disadvantages. Attention in inflammation research has therefore focused on the development of smal l molecular weight inhibitors of TNF alfa production. A phospholipid-like synthetic molecule, ONO 2, was recently found to suppress lipopolysaccharide (LPS)-induced TNF alfa blood level. The mechanism of its activity is currently unknown. Since no endogeno us phospholipids are yet known to inhibit TNF alfa? production, we hypothesize that ONO 2 suppresses TNF alfa? via a novel pathway. The objective of the proposed research is to elucidate that TNF alfa modulating pathway. Specific aims are identification of the signaling components involved in ONO 2-mediated TNF alfa suppression, including: 1) A putative phospholipid-binding receptor and its endogenous ligand.2) Second messengers and early signaling events at the cell membrane. 3) Intracellular ONO 2-regulat ed signaling proteins.We expect that the information obtained by the proposed study will deepen our understanding of the molecular mechanisms which regulate TNF alfa production and will provide us with insights into how to interfere with this process, in order to treat inflammatory auto-immune diseases as well as other inflammation-linked diseases, in a novel therapeutic approach.'

Call for proposal

FP6-2004-MOBILITY-12
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Coordinator

TEL AVIV UNIVERSITY
Address
Ramat Aviv
Tel Aviv
Israel