Vatatu vakahwina mubairo we2019 weNobel muPhysiology kana Medicine, William G. Kaelin, Mudiki, Gregg L. Semenza naSir Peter J. Ratcliffe vakanga vatohwina mubairo we2016 Lasker muBasic Medicine nebasa ravo rekuti masero anonzwa sei uye anochinja sei. kune hypoxia, saka hazvina kunyanya kushamisa. Vakawana uye vakaziva yakakosha mamorekuru hypoxia-inducible factor 1 (HIF-1). Nhasi tinoda kudzokera kune kwakabva chidzidzo ichi, chinova erythropoietin, kana EPO, chishamiso chemorekuru.
Ndicho chinhu chinonyanya kukosha mukugadzirwa kwemasero matsvuku eropa
Masero matsvuku eropa ndiwo anonyanya kuwanda emhando yemasero eropa muropa, uye ndiyo nzira huru yekufambisa oxygen necarbon dioxide kuburikidza neropa remhuka dzine vertebrates. Erythrocytes inogadzirwa mumwongo wepfupa: Hematopoietic stem masero anotanga kuwedzera uye kusiyanisa kuva madzitateguru emasero eropa akasiyana-siyana, uye erythroid progenitors inogona kuwedzera kusiyanisa uye kukura kuva erythrocytes. Mumamiriro ezvinhu akajairika, mwero wekugadzirwa kwe erythrocyte wakaderera zvakanyanya, asi mukushushikana kwakadai sekubuda ropa, hemolysis, uye hypoxia, chiyero chekugadzirwa kwe erythrocyte chinogona kuwedzerwa kusvika kasere. Muchiitiko ichi, erythropoietin EPO ndechimwe chezvinhu zvakakosha.
EPO ihomoni rinogadzirwa kunyanya muitsvo. Chimiro chayo chemakemikari ipuroteni ine glycosylated. Sei muitsvo? Inenge litre yeropa inoyerera kuburikidza neitsvo miniti yega yega, saka vanogona kukurumidza uye nekugona kuona shanduko yeokisijeni muropa. Kana mwero weokisijeni muropa wakadzikira, itsvo dzinopindura nekukurumidza uye dzinoburitsa huwandu hwakawanda hweEPO. Iyo yekupedzisira inotenderera kuburikidza neropa kusvika kune mwongo, uko inosimudzira kushandurwa kwe erythroid progenitor masero mumasero matsvuku eropa. Masero matsvuku eropa akura anobudiswa mumwongo achipinda mugadziriro yeropa kuti avandudze kukwanisa kwomuviri kusunga kuokisijeni. Apo itsvo dzinonzwa kuwedzera kweokisijeni muropa, dzinoderedza kugadzirwa kweEPO, izvo zvozoderedza kuwanda kwemasero matsvuku eropa mumwongo wemapfupa.
Izvi zvinogadzira yakakwana kugadzirisa loop. Zvisinei, vanhu vanogara pakakwirira uye vamwe varwere anemia vanowanzosangana nemamiriro ekuramba akaderera eropa reokisijeni, izvo zvisingakwanisi kupedza kutenderera kwepamusoro uye kukurudzira itsvo kuti irambe ichibudisa EPO, kuitira kuti EPO yeropa iwedzere kudarika vanhuwo zvavo.
Zvakatora makore anoda kusvika 80 kuti zvifukunurwe
Sezvizhinji zvakawanikwa zvakawanikwa, kunzwisisa kwesainzi nezveEPO kwange kusiri kufamba zvakanaka, paine mibvunzo nematambudziko munzira. Zvakatora makore anoda kusvika makumi masere kubva papfungwa yeEPO kusvika pakugadzwa kwekupedzisira kwemamorekuru chaiwo.
Muna 1906, masayendisiti echiFrench Carnot naDeflandre vakabaya tsuro dzemazuva ose neserum yetsuro anemic uye vakawana kuti masero matsvuku eropa muplasma yetsuro dzakajairika akawedzera. Vaidavira kuti zvimwe zvinhu zvinosetsa zviri muplasma zvaigona kukurudzira uye kuronga kugadzirwa kwemasero matsvuku eropa. Iyi yaive yekutanga EPO concept prototype. Nehurombo, mhedzisiro haina kudzokororwa mumakumi emakore akatevera, zvakanyanya nekuti kuverenga kwemasero matsvuku eropa matsva kwanga kusiri kwechokwadi.
Reissmann naRuhenstroth-Bauer's parabiosis experiment muna 1950 yakapa humbowo hwakasimba chaizvo. Vakavhiya vakabatanidza masisitimu ekufambisa kwemakonzo maviri mhenyu, vachiisa imwe munzvimbo ine hypoxic uye imwe ichifema mhepo yakajairika. Nekuda kweizvozvo, mbeva dzese dzakagadzira huwandu hwakakura hwemasero matsvuku eropa. Hapana mubvunzo kuti mune hormone muropa rinokurudzira kugadzirwa kwemasero matsvuku eropa, panobva EPO zita rayo. Kune rumwe rutivi, EPO inonzwa zvakanyanya kune hypoxia.
Chii chinonzi molecule EPO? Zvakatora musayendisiti weAmerica Goldwasser makore makumi matatu kuti apedzisire ajekese dambudziko padanho rebiochemical. Kana mushandi achida kuita basa rakanaka, anofanira kutanga arodza maturusi ake. Basa reEPO nderekukurudzira masero matsvuku eropa matsva, asikuverenga kwekupedzisira hakuna kururama. Iyo inonyanya kukosha inoshanda mumasero matsvuku eropa ihemoglobin ine heme, iyo ine ferrous ion pakati payo. Saka chikwata chaGoldwasser chakanyora masero matsvuku eropa achangozvarwa ane radioactive iron isotopes uye vakagadzira nzira inonzwisisika yekuona chiitiko cheEPO. Izvi zvinoita kuti zvikwanise kutsaura uye kuchenesa zvakanyanya kuderera kweEPO (nanograms pamillilita) kubva kumhando dzemvura yemhuka. Asi kuparadzaniswa kweEPO kwakanga kwakaoma zvikuru. Vakachinja kubva kuitsvo kuenda kune anemic hwai plasma, kune weti yevarwere vane kushayikwa kwesimbi kwakanyanya nekuda kwehutachiona hwehokoworm, uye pakupedzisira, muna 1977, vakachenesa mamirigiramu masere eEPO protein yemunhu kubva pa2,550 litita weti kubva kuvarwere veJapan vane aplastic anemia.
Muna 1985, kurongeka kweprotein uye gene cloning yeEPO yevanhu kwakapedzwa. EPO gene inoisa polypeptide ine 193 amino residues, inova puroteni yakakura inoumbwa ne166 amino acid zvisaririra mushure mekunge chiratidzo chepeptide chadimburwa panguva yekuvanzika, uye ine 4 nzvimbo dzekugadzirisa glycosylation. Muna 1998, iyo NMR mhinduro chimiro cheEPO uye chimiro chekristaro cheEPO uye yayo yekugamuchira yakaoma yakaongororwa. Panguva ino, vanhu vane kunzwisisa kwakanyanya kweEPO.
Kusvikira zvino, kurapwa kweanemia kwaiwanzoda kuwedzerwa ropa kudzorera kushomeka kwemasero matsvuku eropa. Sezvo vanhu vanodzidza zvakawanda nezveEPO, kuibaya jekiseni kuti ikurudzire kugadzirwa kwemasero matsvuku eropa mumwongo wavo pachavo kwakaita kuti dambudziko racho rive nyore. Asi kuchenesa EPO zvakananga kubva mumvura yemuviri, sezvakaita Goldwasser, kwakaoma uye zvibereko zvakaderera. Kutsunga kweprotein yeEPO uye kutevedzana kwemajini kwakaita kuti zvikwanise kugadzira recombinant EPO yemunhu muhuwandu hukuru.
Zvakaitwa nekambani yebiotechnology inonzi Applied Molecular Genetics (Amgen). Amgen yakavambwa muna 1980 iine nhengo nomwe chete, vachitarisira kugadzira biopharmaceuticals neiyo-inobuda nzira dzemolecular biology. Interferon, kukura kwehomoni kuburitsa chinhu, hepatitis B vaccine, epidermal growth factor yaive pakati pemazita anopisa pane yavo rondedzero yezvinangwa, asi hapana chimwe chekuedza uku chakabudirira. Kusvika 1985, Lin Fukun, musayendisiti wechiChinese anobva kuTaiwan, China, akagadzira gene reEPO yemunhu, ndokuzoona kugadzirwa kweEPO yekugadzira vachishandisa tekinoroji yeDNA recombination.
Recombinant EPO yemunhu ine kutevedzana kwakafanana senge endogenous EPO protein, uye zvakare ine yakafanana glycosylation modification. Sezvinongoita, recombinant EPO yemunhu zvakare ine chiitiko cheendogenous EPO. Muna Chikumi 1989, chigadzirwa chekutanga cheAmgen, recombinant human erythropoietin Epogen, chakatenderwa neUS FDA kurapwa kweanemia kunokonzerwa nekusingaperi renal kutadza uye kupererwa neropa mukurapa hutachiona hweHIV. Kutengeswa kweEpogen kwakakwira madhora gumi nematanhatu mumwedzi mitatu chete. Kwemakumi maviri emakore akatevera, Amgen yakatonga musika wekuunganidzazve EPO yevanhu. Epogen yakaunza Amgen $ 2.5 bhiriyoni mumari mu2010 chete. Muna 2018, Amgen's stock market value yaive $128.8 bhiriyoni, zvichiita kuti ive yechisere yakakura kambani yemishonga pasi rose.
Zvakakosha kucherechedza kuti Amgen pakutanga akashanda neGoldwasser kupa mapuroteni eEPO akacheneswa ekutevedzana, asi Goldwasser naAmgen vakakurumidza kudonha nekuda kwekusiyana kwemafungiro. Goldwasser neYunivhesiti yeChicago, vakaita tsvakiridzo yekutanga, havana kumbobvira vafunga kupa patent yehomoni yaakawana, uye saka havasati vawana kana sendi rekubudirira kukuru kweEPO kwekutengeserana.
Iyo -- sei inosimudzira
Patinofema, okisijeni inopinda mumaseru 'mitochondria kutyaira cheni yekufema uye kuburitsa huwandu hukuru hweATP, sosi huru yesimba mumiviri yedu. Vanhu vane anemia havana masero matsvuku eropa akakwana, uye zvinonyanya kuitika ndezvekuti havatore okisijeni yakakwana, izvo zvinoita kuti vanzwe kuneta, zvakafanana nezvinetso zvekufema kwenguva refu. Kana yaiswa jekiseni ine recombinant EPO yemunhu, miviri yevarwere vane anemia inoburitsa mamwe masero matsvuku eropa.takura okisijeni yakawanda, uye gadzira yakawanda yeayo molecule yesimba ATP, zvinobudirira kubvisa zviratidzo.
Zvisinei, vamwe vashandi vemitambo vatangawo kufunga nezve recombinant EPO yevanhu. Kana iyo yakagadzirwa recombinant hormone yeEPO type inoshandiswa kukurudzira muviri wevatambi kuti ubudise mamwe masero matsvuku eropa, zvinokwanisika kuvandudza kukwanisa kwevatambi kuwana oxygen uye kugadzira mamorekuru emagetsi, izvo zvinogonawo kuvandudza kushanda kwevatambi mukutsungirira. zviitiko zvakadai sekuchovha bhasikoro, kureba-kumhanya uye kuyambuka-nyika skiing. Pepa ra1980 muJournal of Applied Physiology rakaratidza kuti zvinokurudzira ropa (erythropoietin, zvinotakura okisijeni zvokugadzira uye kuisirwa ropa) zvinogona kuwedzera kutsungirira ne34 muzana. Kana vatambi vakashandisa EPO, vanogona kumhanya makiromita masere patreadmill mumasekonzi makumi mana nemana nguva shoma kupfuura kare. Muchokwadi, kuchovha bhasikoro uye marathon kwave kuri kukanganisa zvakanyanya kune EPO stimulants. Munguva yeTour de France ya1998, chiremba wechikwata cheSpanish chechikwata cheFestina akasungwa pamuganhu weFrance aine mabhodhoro mazana mana eEPO yakagadzirwazve! Mhedzisiro, hongu, yaive yekuti timu yese yakadzingwa muTour uye yakarambidzwa.
Sangano reInternational Olympic Committee rakawedzera EPO kurondedzero yaro yakarambidzwa paMitambo yeBarcelona ya1992, asi kurongazve kuongororwa kweEPO kwevanhu kwakanga kwakaoma zvokuti Mitambo ya2000 isati yasvika pakanga pasina nzira yekuona nayo kuti vatambi vaiishandisa here. Pane zvikonzero zvakawanda: 1) EPO content mumvura yemuviri yakaderera zvikuru, uye EPO per ml yeropa muvanhuwo zvavo inenge 130-230 nanograms; 2) Iyo amino acid inoumbwa neyakagadzirwa recombinant EPO yakanyatsofanana neyemunhu endogenous EPO protein, chete chimiro che glycosylation chakasiyana zvishoma; 3) Hafu yehupenyu hweEPO muropa inongova maawa 5-6 chete, uye kazhinji haioneki mazuva 4-7 mushure mejojo yekupedzisira; 4) Muyero weEPO wega wega wakasiyana zvakanyanya, saka zvakaoma kumisa chiyero chakakwana chehuwandu.
Kubva 2000, WADA yakashandisa kuyedza weti senzira yega yesainzi yekuongorora yekuona yakananga EPO. Nekuda kwemusiyano mudiki uripo pakati peiyo glycoylated fomu yeartificial recombinant EPO uye yeEPO yemunhu, iyo inochajirwa zvivakwa zvemamorekuru maviri idiki kwazvo uye inogona kusiyaniswa neye electrophoresis nzira inonzi isoelectric focusing, inova ndiyo nzira huru ye Kuonekwa kwakananga kweiyo artificial recombinant EPO. Nekudaro, imwe recombinant EPO inoratidzwa nemaseru akatorwa nevanhu haina mutsauko muglycosylation, saka dzimwe nyanzvi dzakakurudzira kuti exogenous EPO uye endogenous EPO inofanira kusiyaniswa neyakasiyana kabhoni isotope zvirimo.
Muchokwadi, kuchine zvipimo munzira dzakasiyana dzekuedza dzeEPO. Semuyenzaniso, Lance Armstrong, ngano yekuAmerica yemabhasikoro, akabvuma kutora EPO nezvimwe zvinokurudzira panguva yekukunda kwake kunomwe kuTour de France, asi haana kunyatsosimbiswa kuti ane EPO mune chero bvunzo dzedoping panguva iyoyo. Tichiri kufanira kumirira kuti tione kuti “rutsoka rumwe pakakwirira” here kana kuti “rutsoka rumwe pakakwirira”.
Inoita sei Mubairo weNobel
Izwi rekupedzisira nezve kubatana pakati peEPO ne2019 Nobel Prize muPhysiology kana Mushonga.
EPO ndiyo yakajairika mamiriro ekuona kwemuviri wemunhu uye mhinduro kune hypoxia. Naizvozvo, Semenza naRatcliffe, vaviri vakahwina mubairo weNobel, vakasarudza EPO senzvimbo yekutanga kudzidza magadzirirwo ekuona kwesero uye kugadzirisa ku hypoxia. Danho rekutanga raive rekutsvaga maelementi eEPO gene anogona kupindura kuchinja kweokisijeni. Semenza akacherekedza kiyi 256-hwaro isiri-coding kutevedzana pa 3 'kudzika kumagumo kwejini encoding EPO, inonzi hypoxia mhinduro element. Kana kutevedzana kwechinhu ichi kuchishandurwa kana kudzimwa, kugona kweprotein yeEPO kupindura kune hypoxia kunodzikiswa zvakanyanya. Kana iyi yekutevedzana kwechinhu ichibatanidzwa kune yakadzika 3 'magumo emamwe majini asina hukama ne hypoxia, aya akagadziridzwa majini anoratidzawo EPO-kunge activation.pasi pe hypoxia mamiriro.
Ratcliffe nechikwata chake vakabva vaona kuti iyi hypoxic response element haingori muitsvo kana maseru echiropa ane chekuita nekugadzirwa kweEPO, asiwo mune mamwe marudzi mazhinji emasero anogona kushanda pasi pe hypoxic. Mune mamwe mazwi, mhinduro iyi kune hypoxia inogona kunge isiri yakananga kuEPO, asi pane chiitiko chakapararira mumasero. Aya mamwe masero, asina basa nekugadzirwa kweEPO, anofanirwa kunge aine mamorekuru (akadai seakanyorwa zvinhu zvinokonzeresa kubatidza maratidziro ejene) anonzwa shanduko muhuwandu hweokisijeni uye anosunga kune hypoxic mhinduro yekubatidza majini akadai seEPO.
