PROSTANOID BIOSYNTHESIS IN SYSTEMIC MASTOCYTOSIS

系统性肥大细胞增多症中的前列腺素生物合成

• 批准号: 6285863
• 负责人: JOHN Alexander OATES
• 金额: $ 11.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6285863
• 关键词: animal tissue; blood chemistry; cell proliferation; clinical research; drug adverse effect; enzyme activity; enzyme inhibitors; gas chromatography mass spectrometry; hormone biosynthesis; human subject; hypotension; immunocytochemistry; in situ hybridization; isotope dilution method; isozymes; mass spectrometry; mast cell; mastocytosis; medical complication; polymerase chain reaction; prostaglandin endoperoxide synthase; prostaglandins; shock; statistics /biometry; tissue /cell culture; urinalysis

The objective of the proposed research is to examine the biosynthesis of the mast cell mediator, prostaglandin D2, in patients with systemic mastocytosis, and to explore the potential for improvements in the treatment of this disorder. Prostaglandin D2 (PGD2) is the predominant prostaglandin synthesized by the mast cell and this vasodilator contributes to the attacks of hypotension/shock experienced by some patients with systemic mastocytosis. Inhibition of PGD2 biosynthesis with nonselective cyclooxygenase inhibitors (the nonsteroidal anti- inflammatory drugs) has been employed in the treatment of this disorder, but these drugs that block both cyclooxygenase-1 and cyclooxygenase-2 cause major gastrointestinal adverse effects. Either or both of the cyclooxygenase isoforms could be responsible for the biosynthesis of PGD2 in the mast cells of these patients. In the proposed studies, the contribution of and cyclooxygenase-2 to the biosynthesis of PGD2 will be examined, utilizing a selective COX-2 inhibitor, rofecoxib, as a pharmacologic probe for COX-2 dependent PGD2 production. This question also will be addressed by examination of the expression of COX- 1 and COX-2 in mast cells present in the bone marrow and skin of patients with systemic mastocytosis.

拟议研究的目的是检查系统性肥大细胞增多症患者肥大细胞介质前列腺素 D2 的生物合成，并探索改善这种疾病治疗的潜力。前列腺素 D2 (PGD2) 是肥大细胞合成的主要前列腺素，这种血管舒张剂会导致一些全身性肥大细胞增多症患者出现低血压/休克。使用非选择性环氧合酶抑制剂（非甾体类抗炎药）抑制 PGD2 生物合成已被用于治疗这种疾病，但这些同时阻断环氧合酶 1 和环氧合酶 2 的药物会引起严重的胃肠道不良反应。任一或两种环氧合酶亚型可能负责这些患者肥大细胞中 PGD2 的生物合成。在拟议的研究中，将利用选择性 COX-2 抑制剂罗非考昔作为 COX-2 依赖性 PGD2 产生的药理学探针，检查环氧合酶 2 对 PGD2 生物合成的贡献。这个问题也将通过检查系统性肥大细胞增多症患者的骨髓和皮肤中存在的肥大细胞中 COX-1 和 COX-2 的表达来解决。