Prostaglandin D2 Receptor Function

Vanderbilt University, Nashville TN

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Abstract

Prostaglandin D2 (PGD2) is a cyclooxygenase (COX)-derived metabolite of arachidonic acid that modulates[unreadable] a wide range of inflammatory processes. Evidence suggests that PGD2 plays an important role in[unreadable] inflammation in the central nervous system and may be involved in the pathogenesis of multiple sclerosis.[unreadable] PGD2 levels are markedly increased in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients[unreadable] compared to CSF from other neurological diseases. PGD2 exerts its actions via two G-protein coupled[unreadable] receptors, the classical prostaglandin D2 receptor designated DP and the more recently described[unreadable] chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2 or "DP2"). Each of these[unreadable] receptors is activated by physiologically relevant concentrations of PGD2, but they are distinguished by[unreadable] several criteria, including their activation and blockade by a panel of synthetic ligands, their signal[unreadable] transduction pathways, and their respective tissue distribution. Biological responses to PGD2 are complex[unreadable] and our current understanding of the role of these two receptors in mediating the inflammatory response is[unreadable] incomplete.[unreadable] We hypothesize that activation of the DP receptor plays a critical role in the pathogenesis of MS in a mouse[unreadable] model, experimental autoimmune encephalomyelitis, and theorize that activation of the DP receptor is a[unreadable] critical mediator of the pro-inflammatory effects of PGD2 in MS. To investigate this, we will carry out the[unreadable] following specific aims. In Specific Aim 1, we will characterize a novel signal transduction pathway of PGD2[unreadable] receptors. In Specific Aim 2, we will determine the role of PGD2 receptors in immune/inflammatory cell[unreadable] function. The PGD2-evoked effects on purified microglia, dendritic cells and T-cell populations will be[unreadable] examined. In Specific Aim 3, we will determine the role of PGD receptors in experimental autoimmune[unreadable] encephalomyelitis using receptor selective ligands and transgenic mouse models. In Specific Aim 4, we will[unreadable] examine the expression of COX, PGD synthase enzymes and PGD2 receptors in MS patients.[unreadable] Demonstration of a critical role for PGD2 receptor subtype(s) in the pathogenesis of MS will identify a novel[unreadable] therapeutic target.