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醫學一 A 第二組 組長：林語涵 組員：江佳玟、余庭瑋 唐君豪、夏正杰 徐國原、張家福

The Nobel Prize in Physiology or Medicine 2002 ---- for their discoveries concerning programmed cell death. 醫學一 A 第二組 組長：林語涵 組員：江佳玟、余庭瑋 唐君豪、夏正杰 徐國原、張家福. Sydney Brenner. 約與 Crick 同一年代 DNA → RNA→ 蛋白質 以線蟲做為新的生物模型.

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醫學一 A 第二組 組長：林語涵 組員：江佳玟、余庭瑋 唐君豪、夏正杰 徐國原、張家福

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  1. The Nobel Prize in Physiology or Medicine 2002 ---- for their discoveries concerning programmed cell death 醫學一A第二組 組長：林語涵 組員：江佳玟、余庭瑋 唐君豪、夏正杰 徐國原、張家福

  2. Sydney Brenner • 約與Crick同一年代 • DNA→RNA→蛋白質 • 以線蟲做為新的生物模型 圖片來源http://nobelprize.org/nobel_prizes/medicine/laureates/2002/brenner-autobio.html

  3. H. Robert Horvitz • 發現了線蟲中控制細胞死亡的關鍵基因 • 揭示了這些基因怎樣在細胞死亡過程中相互作用 • 證實了人體內也存在相應的基因 圖片來源http://www.people.com.cn/.htmlBIG5/kejiao/230/9142/9143/20021008/837000

  4. John E. Sulston • 人類基因圖譜之父 • 細胞分化時會經歷一種“程序性細胞死亡”的過程 • 確認在細胞死亡過程中控制基因的最初變化情況 圖片來源http://en.wikipedia.org/wiki/John_E._Sulston

  5. 線蟲Caenorhabditis elegans • 幼蟲1094個細胞→ 成蟲959個細胞 • 生活周期短 • 容易養，體積小，可作大量的操作 • 全身透明 圖片來源http://memo.cgu.edu.tw/chuck/popular-sci/%E7%B7%9A%E8%9F%B2%E4%B9%8B%E6%AD%BB%E7%B5%A6%E9%86%AB%E7%99%82%E7%9A%84%E5%95%9F%E7%A4%BA-2002%E8%AB%BE%E8%B2%9D%E7%88%BE%E9%86%AB%E5%AD%B8%E7%8D%8E.htm

  6. INTRODUCTION

  7. 維丘 (Rudolph Virchow) Necrosis! Necrobiosis! httpimages.google.com.twimageshl=zhTW&num=10&lr=&cr=&safe=images&q=%E7%B6%AD%E4%B8%98%20virchow&um=1&ie=UTF8&sa=N&tab=wi

  8. Apoptosis 正式出現! 英國愛丁堡大學病理學家: 克爾 (J.F Kerr) 維利(A.H. Wyllie) => 教授麥克!(J. Cormack) 居禮(A.R. Currie)

  9. Differences between apoptosis & necrosis

  10. 凋亡時細胞的主要變化

  11. 細胞凋亡的型態學變化 細胞膜空泡化(blebbing) 細胞固縮(condensation) 圖片來源:http://commons.wikimedia.org/wiki/File:Apoptosis-zh.png

  12. 細胞凋亡的型態學變化 染色質邊聚(margination) 與中聚(centronation) 圖片來源:http://www.answers.com/topic/apoptosis

  13. 細胞凋亡的型態學變化 形成凋亡小體 (apoptotic body) 圖片來源:http://commons.wikimedia.org/wiki/File:Apoptosis-zh.png

  14. 細胞凋亡的型態學變化 凋亡小體 被巨噬細胞吞噬 圖片來源:http://users.wfu.edu/urdaaj4/Cell/index.htm

  15. 磷脂絲胺酸PS (Phosphatidylserine) 細胞凋亡的生化學變化 胞內Ca+濃度上升 • 細胞膜上的磷脂質發出訊號通知周圍細胞 • 內切酶(endonuclease )的活化 • DNA的片段化 • 粒線體的變化 • 凋亡蛋白酵素(caspase)的活化 電泳梯狀條帶

  16. Apoptosis分兩階段 • 分別為initiation phase及execution phase • Initiation phase分成兩種路徑： The Extrinsic (Death Receptor-Initiated) Pathway The Intrinsic (Mitochondrial) Pathway • Apoptotic signalling from the death receptors • 有名受器：CD95 (or Fas)，TNFR1 (TNF receptor-1)

  17. Signaling by Fas (CD95) FADD : Fas-associated death domain DD : death domain DED : death effector domain

  18. TNF receptor signalling TNFR1:Tumour Necrosis Factor Receptor-1 TRADD:TNFR-associated death domain TRAF2:TNF-associated factor2 NF-KB或AP-1 引發發炎反應

  19. FLIP :FADD-like ICE inhibitory protein

  20. Bcl-2 Family By Phil Dash, University of London (D)arrow：apoptotic bodies

  21. ：surfaceof the mitochondria ：act as sensors in cytosol

  22. Cell stress free radical damage growth factor deprivation By Phil Dash, University of London

  23. Mitochondria also play an important role in amplifying the apoptotic signaling from the death receptors

  24. Permeability Transition pore • ( PT pore) • the release of cytochrome C and other pro-apoptotic molecules • Apoptosome formation&activation (apoptotic protease activating factor-1) By Phil Dash, University of London

  25. Caspase cascade • 2.initiator caspase • (8 or 10) • 3.effector caspases • (3 and 6) R. Chris Bleackley and Jeffrey A. Heibein 2001

  26. Caspases and chromatin breakdown

  27. Caspases and chromatin breakdown 1.Inactivation of enzymes involved in DNA repair • PARP, poly (ADP-ribose) polymerase, an important DNA repair enzyme • One of the first proteins identified as a substrate for caspases • Caspase-3 cleavage PARP

  28. Caspases and chromatin breakdown 2. Breakdown of structural nuclear proteins • Lamins are intra-nuclear proteins • Maintain the shape of the nucleus and mediate interactions between chromatin and the nuclear membrane • Degraded by caspase-6

  29. Caspases and chromatin breakdown 3. Fragmentation of DNA • CAD, caspase activated DNase, fragment DNA into nucleosomal units • Normally inactivated by ICAD (inhibitor of CAD) • Cleaved by caspase-3 to release CAD

  30. caspase-8 • There are two 70aa-long domains in N’ terminal, conserved from DED (death effector domain) in FADD. • Two DED aggregate when inactive. • Combine with the DED of FADD to activate. • Cleavage PARP, self-activated, activate other caspase such as caspase-3.

  31. 三位得獎者與線蟲研究 • 形態學與生化學變化 blebbing → condensation → buding →margination →apoptosis body PS反轉，caspase活化，endonuclease 活化，DNA fragmentation • apoptosis & necrosis Apoptosis Review • 膜相關路徑 ex:CD95 、TNFR1等受器 • 粒線體相關路徑 ex:Bcl-2 family • caspase 簡介&chromatin breakdown • 應用 自體免疫疾病、癌症治療 ex:smac 的發現

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