5-Oxo-ETE is the most potent eosinophil chemotactic factor among lipid mediators and a potent activator of neutrophils. This raises the possibility that this compound is an important mediator of inflammation, especially in conditions associated with eosinophilia such as asthma, psoriasis and IBD. Increasing evidence suggests that eosinophils in the gastrointestinal tract are the cause, at least in part, of digestive diseases such as IBD and Crohn's. The recent discovery in these labs and those of our collaborator of the angiogenic properties of 5-oxo-ETE and the novel eosinophil chemotactic receptor for PGD2 shapes our plans for the future. The angiogenic effect of 5-oxo-ETE, if confirmed, could have implications in 2 important areas: cardiovascular, in which blood vessel growth could circumvent the need for bypass surgery, and in cancer in which new blood vessels promote the growth of tumors. It is not known if angiogenesis associated with 5-oxo-ETE is mediated by the known receptor or a new 1. Our proposed plans are centered around the following: a) The purification of 5-hydroxy dehydrogenase (5h-dh) with the help of a 5-HETE-based affinity chromatography column and a radiophotoaffinity label; b) The connection between 5-oxo-ETE and endothelial cell migration and angiogenesis will be investigated; c) The design and synthesis of a good 5-oxo- ETE antagonist, which could be extremely useful in dissecting the biological properties of 5-oxo-ETE (eosinophil accumulation vs. angiogenesis) with the eventual therapeutic application in asthma and other inflammatory diseases and cancer; d) We termed the new PGD2 receptor, the D?2 receptor; DP] being the classical receptor mediated by cAMP. The characterization of the new receptor with the synthesis of selected PGD2 analogs such as 15-deoxy-A12'14-PGD2. and 15-deoxy-A12>I4-PGJ2 is planned. The 15R-Me-PGD2 is 5 times more active than PGD2 and completely selective for the DP2 receptor. A radioligand with high specific activity will be prepared to establish a binding assay. The long range plan is to provide a roadmap for the involvement of 5-oxo-ETE and the DP2 receptor in diseases and to design the appropriate antagonists to 5- oxo-ETE and the DP2 receptor as therapeutic agents.
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