Prostaglandins (PGs) are lipid-derived hormones involved in rapid, localized cellular responses. Their synthesis is catalyzed by the action of the PG-H synthases, (cyclooxygenases COX-1 and -2). The non-steroidal anti-inflammatory drugs (NSAIDs), which are used for treating inflammatory diseases including arthritis; pain, clotting disorders, and cancer inhibit these enzymes. Despite the widespread use of NSAIDs, our understanding of PG function during physiological and pathological processes is incomplete. Using COX-1 and COX-2 deficient mice, and normal fetal thymus treated with NSAIDs and PG analogs in organ culture the investigator demonstrated a critical role for PGs in T-cell development. The constitutively expressed COX-1 enzyme was required for efficient T-cell development at the CD4-8- to CD4+8+ transition. COX-2 was specifically expressed in a subset of medullary epithelial cells. COX-2 was required during two steps of T-cell development, early thymocyte proliferation and differentiation, during maturation to the CD4 helper lineage. The applicant's goal is to understand the role of PG signaling in T-cell differentiation and selection. To achieve this, the investigator will first determine which cells produce and respond to PGs, and which molecules are involved in PG response and regulation. Whether PGs play a role in gamma-delta T-cell, NK T-cell, NK cell, and thymic dendritic cell development will be determined. Finally, whether PGs mediate their action by promoting cellular survival, proliferation or differentiation, will be determined. These questions will be addressed using COX-1, COX-2, and prostanoid-receptor deficient mice and fetal thymic organ culture.
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