1982年诺贝尔生理学医学奖—关于前列腺素和有关活性物质发现PPT文档.ppt
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1、,1982年十月十一日星期一,位于瑞典斯德哥尔摩的卡洛琳斯卡研究院(Karolinska Institute)正式宣布將本年诺贝尔生理医学奖給两位瑞典籍及一位英国籍的科学家,推崇他們在前列腺素(prostagladin)方面的研究所作的贡献。这三位得奖者是英国的范恩(J.R.Vane),五十五岁,现任英国威尔康研究所(Wellcome Research Laboratories)主任;瑞典的塞缪尔森(B.Samuelsson),四十八岁,卡洛琳斯卡医学院院长及卡洛琳斯卡研究院院长以及今年六十六岁的柏格斯壮(S.Bergstrm)。柏格斯壮博士同时还身兼诺贝尔基金会的董事长,不过那只与基金会的行
2、政业务有关,与得奖者的选拔过程无涉。,Sune K.Bergstrm Autobiography,I was born January 10th,1916 in Stockholm,Sweden.,1946-47,Research Fellowship,Basel University,Basel,Nobel Laureate in Physiology or Medicine,Stockholm,Bengt I.Samuelsson Autobiography,I was born in Halmstad,Sweden,on may 21,1934.After attending publi
3、c schools I studied medicine at the University of Lund where I met my wife Karin(Bergstein).We have one son(Bo)and two daughters(Elisabet and Astrid).After a few years in Lund I moved to Karolinska Institutet in Stockholm in order to do graduate work in biochemistry in parallel with medical studies.
4、In 1960 I finished my dissertation and became docent in medical chemistry.A year later I also obtained my MD degree from Karolinska Institutet.In 1967 I was appointed professor of medical chemistry at the Royal Veterinary College in Stockholm,and after a few years I moved back to Karolinska Institut
5、et to become professor and chairman of the department of physiological chemistry.Concurrently with my research positions I have also held administrative posts.I was dean of the medical faculty from 1978 to 1983,and is presently rector of Karolinska Institutet.,Member of the Royal Swedish Academy of
6、Sciences(1981),Foreign Honorary Member of the American Academy of Arts and Sciences(1982),Honorary Member,Swedish Medical Association,Stockholm,Sweden(1982),Memberships and Honors,John R.Vane Autobiography,I was born in Tardebigg,Worcestershire,on the 29th March 1927,one of three children,with an el
7、der sister and brother.My father,Maurice Vane,was a son of immigrants from Russia and my mother,Frances Vane,came from a Worcestershire farming family.At the age of 12,my parents gave me a chemistry set for Christmas and experimentation soon became a consuming passion in my life.Shortly afterwards,m
8、y father,who ran a small company making portable buildings,erected a wooden shed for me in the garden,fitted with bench,gas and water.This became my first real laboratory.In 1944 I move to the University of Birmingham to study Chemistry.However,the enthusiasm with which I had approached,experimentat
9、ion in Chemistry in the garden shed was soon dampened,for at university experimentation was nonexistent.At this stage that I began to realise that my interest lay not in chemistry but more in experimentation.Thus,when Maurice Stacey,the Professor of Chemistry,asked me what I wanted to do when I grad
10、uated,I said anything but chemistry.Stacey then told me that he had received a letter that morning from Professor Harold Burn in Oxford asking whether he could recommend another young chemist(he had sent one the previous year)to go to Oxford to be trained in pharmacology.Without hesitation I grasped
11、 the opportunity and immediately went to the library to find out what pharmacology was all about!That brief exchange with Stacey reshaped my whole career.,I went to Burns department in 1946.If anyone can be said to have moulded the subject of pharmacology around the world,it is he.His laboratory bec
12、ame the most active and important centre for pharmacological research in the U.K.and the main school for training of young pharmacologists.It was his energy and inspiration that set my career into one of adventure in the fields of bioassay and pharmacology.After qualifying for a B.Sc.in pharmacology
13、,I spent a few months in Sheffield University as a research worker in the pharmacology department but then went back to Oxford to the Nuffield Institute for Medical Research in order to study for a D.Phil.with Dr.Geoffrey Dawes.In 1953 I complete my doctorate.Oxford was also an important milestone f
14、or it was there that my wife and I made our first home,and it was there that my daughters Nicola and Miranda were born.In 1953,I joined the Department of Pharmacology at Yale University as Assistant Professor in Pharmacology,but after 2 years we returned to the U.K,where I started work with Professo
15、r W.D.M.Paton at the Institute of Basic Medical Sciences of the University of London.I stayed there for 18 years,progressing from Senior Lecturer to Reader to Professor of Experimental Pharmacology.In the mid-1960s,our attention was focused on prostaglandins,leading in 1971 to the forging of the lin
16、k between aspirin and the prostaglandins.In 1973,I was offered the position of Group Research and Development Director for The Wellcome Foundation.1974 Fellow of the Royal Society.1977 Albert Lasker Basic Medical Research Award.1982 Nobel Laureate in Physiology or Medicine,Stockholm,大约在半个世纪前,两位美国妇产科
17、医生发现人类新鲜的精液中含有一种未知成分,会引起子宮肌肉的收缩。随后高布拉特(M.W.Goldblatt)在英国与瑞典的冯欧拉(S.U.von Euler)几乎同时发现精液不仅能引起子宮肌肉的收缩,注射到动物身上还有降低血压的效果。1935年,冯欧拉初步鉴定在精液中那些有生理活性的物质是属于一种脂溶性的有机酸,便命名为前列腺素,这个命名并不十分对,因为前列腺素是由精囊而非前列腺分泌到精液中的。无论如何,这个名字现在已经被大家接受,可算是科学界一个积非成是的例子。,冯欧拉接着就试着要纯化这个有趣的成分,但发现纯化的过程极端困难,而进展缓慢,当然这部,分也是受到当时分离技术的限制。直到1947年柏
18、格斯壮出现后,冯欧拉便鼓励这位年轻人向这个问题挑战,柏格斯壮接受了这个劝告,在往后的三十五年里便全心全意地沉浸在前列腺素的研究里。不仅如此,他还引领了另一名学生塞缪尔森,也走进了这个复杂而奥妙的领域中。冯欧拉后來因为研究交感神經传导物质,与爱克斯洛(J.Axelrod)及凯斯(B.Katz)合得了1970年的诺贝尔生理医学奖。柏格斯壮花了十年的努力才在纯化工作上有了一些突破,1957年,他的研究小組首先纯化出两种前列腺素的结晶,往后借助了当时刚刚萌芽的一些新技术,如气体色层分析(gas chromatography)、质谱仪(mass,spectroscopy)和X光分析等,还花了五年的时间才
19、把那两种前列腺素的化学结构決定出來,并且命名为前列腺素E1及F1阿尔发(见图一)。柏格斯壮同时发现前列腺素实际上不只两种,还有许多结构相似的化合物也包含其中,现在已知的前列腺素系列已经超过二十种以上。,1963年,柏格斯壮接任卡洛琳斯卡医学院院长(现任为他的学生,与他同得诺贝尔奖的塞缪尔森)后,他又分离出一些前列腺素家族其他的份子,同时与塞缪尔森一起证实前列腺素是由身体內一些非饱和脂肪酸经过氧化作用而得。其中研究比較清楚的是花生油烯酸(arachidonic acid)所衍生的系列(见图二)。,花生油烯酸是动物细胞膜上的重要組成之一,但是人体无法自行合成,必须依赖外界供给,所以是一种必需脂肪酸
20、。一般說來,它是由非饱和性植物油中的亚麻油酸经人体吸收后代谢而成。平时保存在細胞膜的磷脂中,当有需要的时候,细胞膜上的磷脂水解就会把花生油烯酸释放出來,作为生成各种前列腺素的原料。因此,前列腺素在体內的作用是否正常,与日常饮食摄取脂肪的种类与数量有密切的关系。,长久以來,人們对前列腺素在体內组织分布的情形就很有兴趣,但一直弄不清究竟前列腺素只是花生油烯酸代谢中一个不稳定的中间产物,或是它本身有生物意义的最终产物,范恩在1967年发展出一套灵敏的测试方法,才使科学家有办法追踪前列,腺素在体內的来龙去脉。这个方法便是表面灌流(supraperfusion method)法把待测物质直接灌流到胃壁肌
21、肉条上,记录肌肉收缩的情形。这个方法因为待测物质不会被一般灌流溶液稀释,因此灵敏度很高,又因为作用直接,可以测到许多短命的中间产物的生物活性。这是范恩对前列腺素研究所作的一个重要贡献,当时他是英国皇家外科学院(Royal College of Surgeons)实验药学系教授,到了1973年他转到威尔康研究所任所长职务迄今。,1969年,范恩在患过敏症的兔子肺部分离出一些物质,能引起动脈的收缩,因此命名为兔子动脈收缩物质(rabbit aorta contracting substance),而阿斯匹林却能抑制这种因过敏反,应所释放出的物质。随后范恩又发现,阿斯匹林和一些其他消炎物质在体內会抑
22、制前列腺素的合成,这使我们对前列腺素的了解又向前迈进一大步。阿斯匹林百年来便是医生的万灵丹,它有镇痛、解热、消炎等作用,但一直沒有人知道为什么阿斯匹林有这些药效,因此范恩这一发现首次为阿斯匹林的作用提供了一个理论基础,而且对人体发热、痛觉的作用机制提供了一个有力的探讨工具。现在,我们知道阿斯匹林能够抑制花生油烯酸环氧化在前列腺素合成的过程中极为重要,一旦活性被抑制,会影响到大部分前列腺素的合成。除了阿斯匹林以外,另一个治风湿性关节炎的藥indomethacin也有类似阿斯匹林的效果,抑制前列腺素的合成,这个发现也许对了解风湿性关节炎的成因有所帮助。,接下來的五年是前列腺素研究的丰收时期,首先是
23、范恩注意到兔子动脈收缩物质还会引起血小板的凝集,塞缪尔森此时已接替柏格斯壮为卡洛琳斯卡医学院院长,进一步自其中分离一种前列腺素(命名为H),前列腺素H对促进血小板凝集的作用与使动脈收缩的能力与原來兔子动脈收缩物质不同,这显示兔子动脈收缩物质中必含有一些其他的成分具有不同程度的上述两种生物活性。经过努力的研究后,塞缪尔森终于找到了另一种物质,命名为凝血腺素(thromboxane,简写作TxAz),TxAz能引起动脈的強烈收缩,并会使血小板凝集。原來范恩所分离出的兔子动脈收缩物质是前列腺素H与凝血腺素的混合物。,是否凝血腺素在循环系统中有时会引起血栓等致命的疾病來?有无任何预防或治疗的方法呢?1
24、976年,范恩的研究小組再度获得重大的突破。他们发现前列腺素H在血管壁上会被转变成另一种前列腺素,這种新发现的物质作用与凝血腺素刚好相反,不仅能放松血管壁,而且还会抑制血小板的凝集,范恩于是命名这个新的物质为前列腺素I2(prostacyclin)。现在大家都认为,前列腺素H在体內有两条路可走,一条转变为凝血腺素,加強血管收缩、加速血小板凝集;另一条路则转变为抗凝血腺素,有恰恰相反的效应。而凝血腺素主要由血小板所合成分泌到血液中,抗凝血腺素则由血管壁上的细胞所合成,这两种成分的作用互相抵抗,达到一个平衡,由这个平衡的程度來决定血管弛张,的程度。由于这两种前列腺素在水溶液中半衰期太短(仅30秒)
25、,因此是相当典型的区域性激素,事实上绝大多数的前列腺素作用都是属于这一类,具有相当的区域性。,凝血腺素与抗凝血腺素的发现,使得我們对身体如何控制血液凝結的作用机制有了更进一步的了解,同时还对一些疾病的治疗提供了一个新的方向。像抗凝血腺素将來就可能用來治疗血栓、控制血压或治疗心脏病用,目前许多药厂就正在全力合成各种抗凝血腺素的衍生物,希望找到一种长效而药力较弱(太強了身体也受不了)的抗凝血腺素。事实上,最近范恩已经和英国的戴维森(J.Davison)合作,探讨在开心手术中是否能用抗凝血腺素來防止血液凝集,初步结果相当成功,至于,抗凝血腺素其他方面的应用,则仍有待进一步的研究。到目前为止,将前列腺
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