1997 nobel prize in physiology or medicine
DESCRIPTION
1997 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE. Stanley B. Prusiner’s Presentation Speech. A 班第一組 人員分配. 演講稿吳昭輝 歷史林佳葳 機制朱映慈 疾病王泰元 治療方式林玠鴻 News 張維容. What is prion?. An infectious protein can cause fatal dementia-like diseases Do not possess a genome - PowerPoint PPT PresentationTRANSCRIPT
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1997 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE
Stanley B. Prusiner’s
Presentation Speech
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A 班第一組 人員分配
演講稿 吳昭輝 歷史 林佳葳 機制 朱映慈 疾病 王泰元 治療方式 林玠鴻 News 張維容
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What is prion?
An infectious protein can cause fatal dementia-like diseases
Do not possess a genome Can replicate without a genome There is prion protein in both diseased and h
ealthy individuals But their three-dimensional conformation are
different Replicate by a chain reaction-like process
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Prion Diseases
Which are discovered earlier than prion is discovered
Which are fatal because of the destruction of brain
Which are contagious
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Examples of prion diseases
Scrapie Kuru Mad cow disease
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Arises of prion disease
Spontaneously Be triggered by infection Occur as a consequence of hereditary
predisposition
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Steps of finding prion
Prusiner decided to purify the infectious agent
Prusiner find that the agent consisted only of a protein
Prusiner name the infectious agent with Prion
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Practical ways
Make us better understand the pathogenesis of common demetia
Alzheimer’s disease
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1913
1930中歐羊搔癢症磨蹭磨蹭
德國修道院發病後三個月就死亡、腦部受損Creutzfeldt+Jakob= Creutzfeldt-Jakob disease (CJD)
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1950Kuru (克魯病)新幾內亞東部高地的南富雷女人和小孩吃食其親人屍體漸進性的消瘦,步態不穩, 不自主的顫抖、痙笑,一年 內致死。 加得賽克 Carleton Gajdusek (1976)
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1960
1970
愛爾波以放射線照射的方法抑制核酸的作用病原體在沒有核酸的情況下,增加數量
牟絲在病羊腦部切片中發現一種蛋白質纖維普西納搶先發表1942 出生、美國人
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1986英國狂牛症( mad cow disease )從 1979 年開始使用骨粉( bone meal )1988 年宣佈禁止使用骨粉。
1992狂牛症達到巔峰每個月約有 3,500 頭,全年總計 4 萬頭牛隻因而死亡共 16 萬 5 千頭牛以上死亡 潛伏期
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PrPc PrPsc
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比較
PrPc
不致病
螺旋型 (多阿髪結構 )
會被 protease 分解
可溶性
PrPsc
致病
40% 褶板
不會被 protease 分解
不可溶
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PrPc 原本的功用
神經細胞或少數白血球細胞上 的正常醣蛋白 glycoinositol phospholipids 心臟節律或睡眠調節 銅離子
Prsc 可能結合 plasminogen 空洞
PrPSC如何致病
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人類疾病
疾病名稱 發病機制
Kuru (Fore people) 經由食人儀式感染
Iatrogenic Creutzfeldt-Jakob disease 含 prion 的生長激素或硬膜移植等感染
Variant Creutzfeldt-Jakob disease 由牛隻上的 prion感染 ?
Familial Creutzfeldt-Jakob disease PrP 的基因突變
Sporadic Creutzfeldt-Jakob disease 體突變或是 PrPC 的自發性轉換 ?
Fatal familial insomnia PrP 的基因突變
Gerstmann-Sträussler-Scheinker disease
PrP 的基因突變
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Kuru
潛伏期 : 平均 12年
疾病症狀 ( Daniel Gajdusek ,1996 )
走動期 :顫抖 ; 協調 , 語言能力逐漸喪失 久坐期 :情緒不穩定 ;嚴重的運動失調 末 期 :發音困難 ;潰瘍 ;大小解無法自制 ;
吞嚥困難
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Fatal familial insomnia (FFI) 發病年齡 : 30歲 ~60歲
發病到死亡 : 7~36 個月1. 失眠頻率增加 , 恐慌 – 四個月2. 幻覺 – 五個月 3. 完全失眠 ,體重急速下降 – 三個月 4. 癡呆 ,從沒反應到說不出話來 – 六個月5. 死亡
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動物疾病
疾病名稱 發病機制
Scrapie ( 羊搔症 ) 同類動物感染或自發產生 ?
Bovine spongiform encephalopathy ( 狂牛症 )
Infection with prion-contaminated MBM
Transmissible mink encephalopathy (水貂 )
經由牛或羊的 prion感染
Chronic wasting disease (騾 ,鹿等 ) 未知
Feline spongiform encephalopathy (貓 )
Infection with prion-contaminated MBM
Exotic ungulate encephalopathy (大型羚羊 )
Infection with prion-contaminated MBM
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Scrapie
影響綿羊或山羊的神經系統 造成搔癢感 因搔癢刮下自身羊毛 lip-smacking, strange gaits, convulsive collap
se
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Bovine spongiform encephalopathy (BSE) 神經系統衰退 緊張 , 焦躁 出現怪異姿勢 牛奶產量減少 體重減輕 死亡
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目前概況
• 由於病源體特殊,並無明確的醫療方法• 其他如阿茲海默症等腦部病變疾病,亦存在類似狀況
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傳統化學藥物
奎那克林 (quinacrine, 即 quinacrine hydrochlori, 中文又稱虐滌平 )
氯普馬乙 (chlorpromazinev﹐抗精神病藥物﹐有鎮靜作用。 )
可阻礙惡性普恩蛋白團塊在受感染的陪有中的老鼠細胞中的形成。
已知這兩種藥品可以經過血流進入腦中。 然而有研究顯示,團塊並非發病的主要病徵或病灶
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構想中的藥物:從 PrPC 轉變到 PrPSc 的過程下手
• PrP 蛋白質藉由藥物的附著,而穩固在 PrPC狀態 • 修改 protein X (molecular chaperone) • PrPC的仿作藥物 (但改變附著位? ) • 直接破壞 PrPSc的結構 : Unfoldin 蛋白
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構想中的藥物:抗體
• 有單株抗體可以抑制 PrPSc 的複製:抗體免疫或體液免疫
• 正常和異常 PrP 蛋白的辨認性?副作用?
• 2004 的老鼠實驗: Multiple antigenic peptides(MAPs)
• 促進自體免疫系統辨認多肽序列
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從起源下手:新品種牛羊?
基因於 171 的位置上有” Arg/Arg polymorphism”的羊,對羊搔癢症免疫。
所以 Arg171 可以使牛羊對 PrPSc免疫? Arg171 、 Protein X 以人工生殖技術,大量生產此類表現形牲畜 或者乾脆除掉 PrP 蛋白基因?
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狂牛病的檢測
新抗體檢測 瓶頸 策略 提高組織裡的 PrPSc含量 著重在蛋白質形狀的細節而非數量
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prion蛋白的光明面
觀察 成年老鼠的骨髓細胞 實驗 從野生型 (wild-type) 的老鼠身上取下骨髓細
胞,並將其純化成 A.含有與 B.不含普里昂蛋白質的細胞 ,植入老鼠體內
結果 發現 A. 長生命期及短生命期的造血幹細胞 B.短生命期的造血幹細胞 結論 普里昂蛋白質是野生型老鼠體中長生命期造血幹細胞的標記
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實驗 A.野生型及 B.無普里昂蛋白質的老鼠骨髓細胞移植入被致命射線照射的老鼠,之後再移植,共三次
結果 A.不會有下降的情況 B.老鼠的自我更生能力急遽下降,可產生普里昂蛋白質的反轉錄病毒感染 可解救此缺陷
結論 普里昂蛋白質對造血幹細胞的自我更生有其相當的必要性
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我們都錯怪 PrPSC了?!
抑制 PrPSC的堆積 失敗 由 PrPC 下手 實驗 剔除小鼠的 PrPC 基因而無法產生 PrPC,即使感染後,不會產生中樞神經的病變 ,甚至另一種可能是海綿狀腦組織可以逐漸修復
結論 神經系統病變的關鍵其實在於神經細胞內 PrPC的轉變