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Kenneth K. Wu 伍焜玉

研究生涯與社會關懷之經歷. Kenneth K. Wu 伍焜玉 Distinguished Investigator and President, National Health Research Institutes (NHRI), Taiwan Member, Academia Sinica, Taiwan. 中學時代. 大學時代. 醫學系（醫科）. 前二年 醫預科 （動植物學、物理、化學、有機化學、英文、歷史（近代史）） 3-4年 基礎醫學 （解剖、組織、生化、生理、毒理、病理、公共衛生、微生物、免疫） 5-6年 臨床醫學 （內科學、外科學等）

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Kenneth K. Wu 伍焜玉

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  1. 研究生涯與社會關懷之經歷 • Kenneth K. Wu 伍焜玉 • Distinguished Investigator and President, National Health Research Institutes (NHRI), Taiwan • Member, Academia Sinica, Taiwan

  2. 中學時代

  3. 大學時代

  4. 醫學系（醫科） • 前二年 醫預科（動植物學、物理、化學、有機化學、英文、歷史（近代史）） • 3-4年 基礎醫學（解剖、組織、生化、生理、毒理、病理、公共衛生、微生物、免疫） • 5-6年 臨床醫學（內科學、外科學等） • 7年 實習

  5. 開業 醫學系 專業醫師訓練 研究、教學 公共衛生 政策

  6. 赴美國入研究所：微生物及免疫

  7. New Haven 在美國New Haven生活

  8. 進入臨床專科醫師訓練 • 內科學 • 內科血液腫瘤科

  9. 在美國愛荷華市生活 Iowa City

  10. 選擇血栓及血小版研究 血栓 動脈血栓 靜脈血栓 心血管疾病腦中風 肺血管阻塞

  11. Formation of an advanced, complicated lesion of atherosclerosis N Engl J Med. 1999;340:115-126

  12. 動脈血栓 靜脈血栓 血栓之成分 凝結蛋白質 血小板 紅血球 血小板 凝結蛋白質 血管壁硬化破裂 白血球

  13. 血小板之活性在動脈血栓扮演什麼角色？

  14. 個別血小板 刺激後 凝結並釋放出Active materials 血栓成分 血管壁傷害 （發炎） 血管病變

  15. 血小板（150,000-450,000 / ml） 數量減少 數量增多 功能減低 出血 血栓 出血

  16. 血小板功能增加時是否增加血栓？

  17. Lancet. 1974;2:924-926. A new method for the quantitative detection of platelet aggregates in patients with arterial insufficiency. Wu, K.K., Hoak, J.C.

  18. Thromb Haemost. 1976;35:702-711. Spontaneous platelet aggregation in arterial insufficiency: mechanisms and implications. Wu, K.K., Hoak, J.C.

  19. Ann Intern Med. 1978;88:7-11. Platelet hyperaggregability and thrombosis in patients with thrombocythemia. Wu, K.K.

  20. Aspirin (阿斯匹靈)

  21. Salix alba L.

  22. Willow bark extract • Hippocratea and other Greek physicians mentioned it. • Chinese used it over 2000 years ago. • 18th century: -- Japanese used it to treat emperor’s tension headache -- Rev. Edmund Stone used it to trat patients with fever and pain.

  23. Edmund Stone Philosophical Transactions. 1763;53:195-200. (Chipping Norton, London, Oxfordshire)

  24. Johann Buchner (Germany), 1828 Salicin isolation • Raffaele Piria (France), 1836 Conversion of salicin to salicylic acid (SA) • Felix Hoffmann (Germany), 1899 Derivatization of SA to aspirin

  25. Early aspirin product

  26. Aspirin (阿斯匹靈)減少血小板功能

  27. 服用Aspirin 引起出血

  28. Aspirin 引起出血是因為它能抑止血小板功能

  29. Aspirin 能抑止血小板功能，是否能用來治療血栓疾病？

  30. Ann Intern Med. 1978;88:7-11. Platelet hyperaggregability and thrombosis in patients with thrombocythemia. Wu, K.K.

  31. 適量Aspirin (65 mg-325 mg) 能減少血栓形成，預防病人血栓疾病

  32. Aspirin 抑止前列腺素 (Prostaglandin)之產生

  33. Discovery and purification of cyclooxygenases (COX) 1933-1934 – Discovery of prostaglandins (Goldblatt, von Euler). 1960s – Isolation and structural analysis of PGs (Berström, Samuelsson). 1970s – COX was purified from ram seminal vesicles (Bill Lands). 1980s – COX cDNA was cloned (Bill Smith). This COX is now known as COX-1. 1990 – COX-1 X-ray crystal structure (Garavito)

  34. Cloning of COX-2 • Phorbol ester-induced genes in NIH 3T3 (Hershman’s group) • Src-induced genes in chick embryo cells (Simmon’s group) • (~60% sequence homology with COX-1)

  35. Nature Structural & Molecular Biology. 2000;7:448.

  36. Phospholipids (PC) Phospholipase A2 Arachidonic acid + LysoPC COX-2 or COX-1 PGG2 + PGH2 PGI synthase TXA synthase PGI2 TXA2 6-keto-PGF1α TXB2

  37. Arachidonic acid (AA) Aspirin COX-1活性 PGH2 TXA synthase TXA2 血小管凝結 血管病變

  38. AA Aspirin COX-2基因表達 PGH2 PGE2 etc. 發炎、癌症

  39. Proc. Natl. Acad. Sci. USA. 1991;88:2384-2387. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells Wu KK, Sanduja R, Tsai AL, Frehanoglu B, Loose-Mitchell DS.

  40. Aspirin and sodium salicylic inhibit COX-2, IL-4 and IL-6 expressions with equal potency at the transcriptional level. • They inhibit gene transcription by blocking binding of C/EBPb and c-Rel (NF-kB) transcription activators

  41. Aspirin and salicylate IL-1b PMA C/EBPb COX-2 promoter COX-2 PGE2

  42. C/EBPβ mutants PKA ERK T235 S288 1 345 N C T266 S325 RSK CaMKIV Mutants: T235A (ERK) T266A (RSK) S288A (PKA) S325A (CaMKIV)

  43. Transactivator Streptavidin Biotin Agarose DNA probe Western analysis

  44. FLAG Vector WT T235A T266A S288A S325A

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