Prostaglandins (PGs) are small bioactive lipid mediators generated by the cyclooxygenase (Cox) enzymes. The concept we developed is that PGs are not simply causes of pain and fever, but are critical mediators of immune regulation. A newly discovered Cox product called 15d-PGJ2, as well as a class of existing synthetic small molecules, are the current subject of much investigation due to their ability to bind and activate a receptor/transcription factor called peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma was formerly a member of the orphan family of nuclear receptors whose natural ligand, 15d-PGJ2, was only recently discovered. The transcription factor PPARgamma, synthetic PPARgamma ligands and the Cox-2 product ISd-PGJ2 have now emerged as central elements in two areas of biology and medicine: lipid metabolism and attenuation of inflammation. Our published data show that both normal and malignant B lineage cells highly express the transcription factor PPARgamma. These cells undergo apoptosis upon exposure to small molecule PPARgamma agonists, including 15d-PGJ2. This supports the emerging concept that PPAR? agonists are anti-inflammatory in nature. The overall hypothesis we wish to test in this next funding period is that PPARgamma, and natural and synthetic PPARgamma agonists, dampen B lymphocyte survival and therefore attenuate normal humoral immune responses, and that the PPARgamma pathway can be targeted as a novel therapy for human B cell lymphoma. The major thrust of this renewal application is to study the mechanisms whereby natural and synthetic PPARgamma ligands affect normal and malignant B lineage cells, especially those of human origin. These studies therefore have high translational potential. The following three questions will be answered to test our overarching hypothesis. 1) Is the mechanism through which PPARgamma agonists kill normal and malignant B lineage cells through NF-kappaB and is this PPARgamma dependent? 2) Where and when is 15d-PGJ2 produced in vivo during an immune response and what are the functional consequences to B lymphocytes exposed to 15d-PGJ2 and to synthetic PPARgamma agonists in vivo? 3) Can PPARgamma agonists be used as potential therapeutics for B cell lymphoma? Addressing these questions will lead to an understanding of how natural and synthetic PPARgamma agonists and PPARgamma regulate B lymphoid elements of the immune system. This will provide insight into how to optimize the use of PPARgamma agonists as anti-B lineage cell strategies in diseases such as periodontal disease and arthritis, and as potential new treatments for malignant B cell lymphoma.
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