{"id":32464,"date":"2019-02-17T01:05:44","date_gmt":"2019-02-16T22:05:44","guid":{"rendered":"https:\/\/bilimvegelecek.com.tr\/?p=32464"},"modified":"2019-02-16T23:07:55","modified_gmt":"2019-02-16T20:07:55","slug":"uzun-omur-kansersiz-yasam-ve-filler-aradaki-baglantiyi-bulun","status":"publish","type":"post","link":"https:\/\/bilimvegelecek.com.tr\/index.php\/2019\/02\/17\/uzun-omur-kansersiz-yasam-ve-filler-aradaki-baglantiyi-bulun","title":{"rendered":"Uzun \u00f6m\u00fcr, kansersiz ya\u015fam ve filler: Aradaki ba\u011flant\u0131y\u0131 bulun"},"content":{"rendered":"

Kanser \u00e7okh\u00fccrelilik kadara eskilere uzansa da her hayvanda ayn\u0131 oranda g\u00f6r\u00fclmez. Mesela fillerde veya t\u00fcys\u00fcz k\u00f6stebek farelerinde m\u00fcthi\u015f nadirdir. Yaban gelinci\u011fi ve k\u00f6pek gibi kimi hayvanlar ise al\u0131\u015f\u0131lmad\u0131k derecede y\u00fcksek oranlarda kansere yakalan\u0131r. Peki neden?<\/span><\/p>\n

1977\u2019de \u0130ngiliz epidemiyoloji uzman\u0131 Richard Peto v\u00fccudu b\u00fcy\u00fck ve ya\u015fam s\u00fcresi uzun hayvanlar\u0131n di\u011ferlerine g\u00f6re daha fazla h\u00fccre b\u00f6l\u00fcnmesine u\u011frad\u0131\u011f\u0131n\u0131, her bir h\u00fccre b\u00f6l\u00fcnmesinin de olu\u015fan yavru h\u00fccrede kendini g\u00f6sterecek k\u00fc\u00e7\u00fck ama g\u00f6zard\u0131 edilemeyecek bir mutasyon riskini beraberinde getirdi\u011fini d\u00fc\u015f\u00fcnd\u00fc. Dolay\u0131s\u0131yla bu mutasyonlardan baz\u0131lar\u0131n\u0131n kansere yol a\u00e7ma riskinden s\u00f6z edilebilirdi. Yani t\u00fcm ko\u015fullar ayn\u0131 oldu\u011funda, daha b\u00fcy\u00fck v\u00fccutlu ve uzun \u00f6m\u00fcrl\u00fc hayvanlarda, k\u00fc\u00e7\u00fck ve k\u0131sa \u00f6m\u00fcrl\u00fc olanlara g\u00f6re kanser riskinin daha fazla oldu\u011funu d\u00fc\u015f\u00fcnmek m\u00fcmk\u00fcnd\u00fc. Fakat Peto bu hayvanlardan baz\u0131lar\u0131n\u0131n sergiledi\u011fi kanser oranlar\u0131na bakt\u0131\u011f\u0131nda kar\u015f\u0131la\u015ft\u0131\u011f\u0131 tablonun tam da \u00f6yle olmad\u0131\u011f\u0131n\u0131 g\u00f6rd\u00fc. Mant\u0131ksal ak\u0131l y\u00fcr\u00fctmesine ayk\u0131r\u0131 gibi g\u00f6r\u00fcnen bu olgu Peto ikilemi olarak adland\u0131r\u0131ld\u0131.<\/span><\/p>\n

Odur budur ara\u015ft\u0131rmac\u0131lar, Peto ikilemini a\u00e7\u0131kl\u0131\u011fa kavu\u015fturmak \u00fczere \u00e7e\u015fit t\u00fcrl\u00fc hayvan\u0131n, \u00f6zellikle de c\u00fcsseli ve uzun \u00f6m\u00fcrl\u00fc olanlar\u0131n genom dizileri \u00fczerinde \u00e7al\u0131\u015fmalar y\u00fcr\u00fct\u00fcyor. Ne var ki hen\u00fcz bir cevap bulunabilmi\u015f de\u011fil. Ele al\u0131nan her bir t\u00fcr sanki Peto ikilemine farkl\u0131 bir a\u00e7\u0131klama getiriyor; bu farkl\u0131l\u0131k da muhtemelen farkl\u0131 ya\u015fam \u00f6yk\u00fclerinden ve farkl\u0131 evrimsel se\u00e7ilim bask\u0131lar\u0131na maruz kal\u0131yor olmalar\u0131ndan kaynaklan\u0131yor.<\/span><\/p>\n

Yine de bu \u00e7al\u0131\u015fmalar, Utah \u00dcniversitesi Huntsman Kanser Enstit\u00fcs\u00fc\u2019nde pediyatri onkolojisi uzman\u0131 Joshua Schiffman\u2019\u0131n g\u00f6r\u00fc\u015f\u00fcne g\u00f6re, insanlarda g\u00f6r\u00fclen kanserlerin tedavisini ve engellenmesini beraberinde getirebilir. Nitekim ara\u015ft\u0131rmalar\u0131n\u0131n sonucunda Schiffman, genetik kanser riski y\u00fcksek -insan- hastalardaki yetersiz ya da bozuk sinyal yollar\u0131n\u0131n ve gen k\u00fcmelerinin, hayvanlar\u0131 kanserden koruyanlarla ayn\u0131 oldu\u011funu g\u00f6sterebilmi\u015f. Dolay\u0131s\u0131yla Schiffman\u2019a g\u00f6re mevcut durumda \u015funu s\u00f6yleyebiliyoruz: \u201cHastalar i\u00e7in yeni ila\u00e7lar geli\u015ftirmek istedi\u011fimizde pe\u015fine d\u00fc\u015fece\u011fimiz proteinler ve molek\u00fcler yollar bunlar olacak; zira do\u011fa kanser direncinde rol alan bu yap\u0131lara deyim yerindeyse fener tutmu\u015f durumda.\u201d<\/span><\/p>\n

Fillerin S\u0131rr\u0131<\/b><\/p>\n

Schiffman\u2019\u0131n ekibi ve i\u015fbirli\u011fi halinde olduklar\u0131 di\u011fer \u00e7al\u0131\u015fma gruplar\u0131, 2015 itibariyle Peto ikileminin fil aya\u011f\u0131n\u0131 \u00e7\u00f6z\u00fcme kavu\u015fturmaya \u00e7ok yakla\u015ft\u0131: Buna g\u00f6re, bu devasa hayvanlarda t\u00fcm\u00f6r bask\u0131lay\u0131c\u0131 <\/span>TP53<\/span><\/i> geninin (veya \u201ct\u00fcm\u00f6r proteini p53\u201d olarak da bilinir) fazladan 20 kopyas\u0131n\u0131n bulundu\u011fu tespit edildi. \u0130nsanda ve di\u011fer pek \u00e7ok hayvanda da bulunan <\/span>TP53<\/span><\/i> normal \u015fartlarda onar\u0131lmas\u0131 m\u00fcmk\u00fcn olmayan, dolay\u0131s\u0131yla h\u00fccreyi kanserli hale getirebilecek DNA hasar\u0131n\u0131 tespit edince, kodlad\u0131\u011f\u0131 p53 proteini arac\u0131l\u0131\u011f\u0131yla kanserli h\u00fccrenin \u00f6l\u00fcm\u00fcn\u00fc tetikler. <\/span>TP53<\/span><\/i> geni mutasyonlu do\u011fan bireylerde Li-Fraumeni sendromu denen ve ya\u015fam s\u00fcresi i\u00e7inde kanser geli\u015ftirme riskini %100\u2019e yakla\u015ft\u0131ran bir hastal\u0131k g\u00f6r\u00fcl\u00fcr.<\/span><\/p>\n

Fillerde g\u00f6r\u00fclen kanser direncinin s\u0131rr\u0131n\u0131 \u00e7\u00f6zmek isteyen ara\u015ft\u0131rmac\u0131lar <\/span>TP53<\/span><\/i>\u2019\u00fcn ekstra kopyalar\u0131n\u0131n h\u00fccre i\u015flevleri \u00fczerindeki etkisini anlamak \u00fczere fil lenfositlerini ve fibroblastlar\u0131n\u0131 DNA hasar\u0131na tabi tuttular. \u0130nsanlardan al\u0131n\u0131p k\u00fclt\u00fcr ortam\u0131nda b\u00fcy\u00fct\u00fclen kanserli h\u00fccre soylar\u0131yla kar\u015f\u0131la\u015ft\u0131r\u0131ld\u0131\u011f\u0131nda bu fil lenfositlerinin ve fibroblastlar\u0131n\u0131n tedavilere \u00e7ok daha etkili cevap vererek kanserli h\u00fccrelerdeki h\u00fccresel \u00f6l\u00fcm\u00fc y\u00fcksek d\u00fczeylerde tetiklediklerini g\u00f6sterdiler. Bu da ekstra <\/span>TP53<\/span><\/i> kopyalar\u0131n\u0131n DNA hasar\u0131na g\u00f6sterilen hassasiyeti art\u0131rd\u0131\u011f\u0131, b\u00f6ylece potansiyel kanserli h\u00fccrenin ekarte edilmesi becerisini g\u00fc\u00e7lendirdi\u011fi bi\u00e7iminde yorumland\u0131.<\/span><\/p>\n

Her bir <\/span>TP53<\/span><\/i> kopyas\u0131n\u0131n oynad\u0131\u011f\u0131 rol\u00fc daha da iyi anlamak \u00fczere Schiffman\u2019\u0131n ekibi bunlardan birer tane ayr\u0131\u015ft\u0131r\u0131p teker teker kanserli insan h\u00fccresi soyuna yerle\u015ftirdi. A\u011fustos 2018\u2019de Utah\u2019ta ger\u00e7ekle\u015ftirilen Uluslararas\u0131 Evrimsel T\u0131p ve Halk Sa\u011fl\u0131\u011f\u0131 Derne\u011fi\u2019nin toplant\u0131s\u0131nda, Schiffman\u2019la birlikte \u00e7al\u0131\u015fan kanser biyolo\u011fu Lisa Abegglen bu i\u015flemin, DNA hasar\u0131na cevaben ortaya \u00e7\u0131kan kanserli h\u00fccre \u00f6l\u00fcm\u00fcn\u00fc, fillere ait <\/span>TP53<\/span><\/i> kopyas\u0131 ta\u015f\u0131mayan soylardakine k\u0131yasla art\u0131rd\u0131\u011f\u0131n\u0131 bildirdi. \u015eimdilerde Schiffman ve ekibi, Technion-\u0130srail Teknoloji Enstit\u00fcs\u00fc ortakl\u0131\u011f\u0131yla, fillerdeki <\/span>TP53<\/span><\/i> kopyalar\u0131n\u0131 nanopartik\u00fcller halinde ba\u015fka hayvanlar\u0131n kanserli dokular\u0131na verip t\u00fcm\u00f6r\u00fcn bu yolla hedef al\u0131nmas\u0131 olas\u0131l\u0131\u011f\u0131 \u00fczerinde \u00e7al\u0131\u015f\u0131yor. Schiffman bir\u015fey s\u00f6ylemek i\u00e7in hen\u00fcz erken oldu\u011funu belirtse de ara\u015ft\u0131rmac\u0131lar PEEL Therapeutics (<\/span>peel<\/span><\/i> fil s\u00f6zc\u00fc\u011f\u00fcn\u00fcn \u0130branicesidir) isimli bir biyoteknoloji \u015firketi kurmu\u015flar bile.<\/span><\/p>\n

Hayvanlarda alternatif bol<\/b><\/p>\n

Fillerin bedenindeki tek gizem bu de\u011fil. Lynch\u2019in laboratuvar\u0131 taraf\u0131ndan y\u00fcr\u00fct\u00fclen 2018 tarihli bir ba\u015fka \u00e7al\u0131\u015fmada fillerin, l\u00f6semiyi inhibe edici (yani faaliyet durdurucu) fakt\u00f6r (<\/span>LIF<\/span><\/i>) olarak bilinen bir ba\u015fka genden daha 11 adet ekstra kopya ta\u015f\u0131d\u0131klar\u0131 g\u00f6sterilmi\u015f. DNA hasar\u0131n\u0131n ortaya \u00e7\u0131kmas\u0131 halinde bu kopyalardan biri olan LIF6, <\/span>TP53<\/span><\/i> taraf\u0131ndan faaliyete ge\u00e7iriliyor. Aktif hale getirilen LIF proteinleri, mitokondriye etki ederek kanserli h\u00fccrenin \u00f6l\u00fcm\u00fcn\u00fc tetikliyor. Yani t\u0131pk\u0131 <\/span>TP53<\/span><\/i> \u00f6rne\u011finde oldu\u011fu gibi bu ekstra kopyalar, fil h\u00fccrelerinin DNA hasar\u0131na kar\u015f\u0131 daha duyarl\u0131 olmalar\u0131n\u0131 sa\u011fl\u0131yor.<\/span><\/p>\n

Kanserin bask\u0131lanmas\u0131nda h\u00fccre \u00f6l\u00fcm\u00fcn\u00fcn tetiklenmesinden ba\u015fka y\u00f6ntemlere ba\u015fvuran hayvanlar da var. Mesela t\u00fcys\u00fcz k\u00f6stebek fareleri (<\/span>Heterocephalus glaber<\/span><\/i>). Bu hayvanlar\u0131n h\u00fccreler aras\u0131 s\u0131v\u0131lar\u0131nda ta\u015f\u0131d\u0131klar\u0131 ilgin\u00e7 bir \u00f6zellik onlar\u0131 t\u00fcm\u00f6r olu\u015fumundan koruyor.<\/span><\/p>\n

\"\"<\/p>\n

Yer alt\u0131nda ya\u015fayan ve boyutlar\u0131 fareninkine e\u015f bu hayvanlar, farelerden farkl\u0131 olarak 30 sene ya\u015farlar; yani yedi kat daha uzun! Ayr\u0131ca neredeyse hi\u00e7 kanser olmazlar. \u00c7al\u0131\u015fmalar k\u00f6stebek farelerinin h\u00fccreler aras\u0131 mesafeyi belli bir seviyede tutarak kanser riskini azaltt\u0131klar\u0131n\u0131 g\u00f6stermi\u015f. Hayvan\u0131n h\u00fccreleri fazla s\u0131k\u0131\u015f\u0131k konuma ge\u00e7ti\u011finde h\u00fccre sinyal yollar\u0131ndan \u00e7ekirde\u011fe daha fazla b\u00f6l\u00fcnmemesi emri gidiyor. K\u00f6stebek fareleri \u2018temas inhibisyonuna a\u015f\u0131r\u0131 duyarl\u0131l\u0131k\u2019 ad\u0131 verilen bu mekanizmay\u0131, h\u00fccre d\u0131\u015f\u0131 ortamda normalin \u00fczerindeki seviyelerde bulunan y\u00fcksek-k\u00fctleli hiyal\u00fcronan\u2019a, yani karbonhidrat yap\u0131s\u0131ndaki bir polimer olan hiyal\u00fcronik aside bor\u00e7lular. Ara\u015ft\u0131rmac\u0131lar bu molek\u00fcl\u00fc y\u0131k\u0131ma u\u011fratt\u0131klar\u0131nda hayvan\u0131n h\u00fccrelerinde t\u00fcm\u00f6r olu\u015fumunun ba\u015flad\u0131\u011f\u0131n\u0131 g\u00f6zlemlemi\u015fler. Peki insanlarda kanseri engellemek ya da tedavi etmek kanserli dokuya hiyal\u00fcronan molek\u00fcl\u00fc vererek m\u00fcmk\u00fcn olabilecek mi? O kadar kolay de\u011fil; \u00e7\u00fcnk\u00fc iki organizman\u0131n kulland\u0131\u011f\u0131 sinyal yollar\u0131 tam olarak ayn\u0131 de\u011fil. Fakat insanlarda t\u00fcm\u00f6rl\u00fc dokuda hiyal\u00fcronan y\u0131\u011f\u0131lmas\u0131n\u0131n meydana geldi\u011fi ve bunun da ila\u00e7 ge\u00e7i\u015fini engelledi\u011fi biliniyor. Dolay\u0131s\u0131yla y\u0131\u011f\u0131n halindeki bu molek\u00fcl\u00fc hedef alan nanopar\u00e7ac\u0131k tabanl\u0131 bir tedavi, ilac\u0131n hedefe (yani t\u00fcm\u00f6re) daha etkin bi\u00e7imde ula\u015fmas\u0131n\u0131 sa\u011flayabilir.<\/span><\/p>\n

\"\"<\/p>\n

Kansersiz ya\u015fam\u0131n s\u0131rr\u0131n\u0131 ele verebilecek son organizmam\u0131z yarasalar. 45 y\u0131ll\u0131k \u00f6m\u00fcrleriyle bu canl\u0131lar t\u0131pk\u0131 filler gibi fazladan <\/span>TP53<\/span><\/i> kopyas\u0131 ta\u015f\u0131yorlar. Fakat uzun \u00f6m\u00fcrlerini bor\u00e7lu olduklar\u0131 bir \u00f6zellikleri daha var: ileri ya\u015flar\u0131na ra\u011fmen ilk halini yani ba\u015flang\u0131\u00e7taki uzunlu\u011funu korumaya devam eden telomerleri (kromozomlar\u0131n ucundaki tekrar b\u00f6lgeleri). Telomerlerdeki k\u0131salma h\u00fccrenin ya\u015flanmas\u0131na ve h\u0131zla \u00f6lmesine yol a\u00e7arken uzun telomer boyu h\u00fccrenin (dolay\u0131s\u0131yla hayvan\u0131n) uzun s\u00fcre ya\u015famas\u0131n\u0131 sa\u011fl\u0131yor. Sahip olduklar\u0131 ekstra <\/span>TP53<\/span><\/i> kopyalar\u0131 da bu s\u00fcre\u00e7te geli\u015febilecek DNA hasarlar\u0131n\u0131 tespit ederek t\u00fcm\u00f6r olu\u015fumunu engelliyor. Daha s\u0131rada 200 y\u0131l\u0131 a\u015fan inan\u0131lmaz uzunluktaki \u00f6m\u00fcrleriyle kutup balinalar\u0131 var\u2026 <\/span><\/p>\n

 <\/p>\n

Kaynak
\n<\/b>Vivian Callier, \u201cSolving Peto\u2019s Paradox to better understand cancer\u201d, <\/span>PNAS<\/span><\/i>, 5 \u015eubat 2019.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Kanser \u00e7okh\u00fccrelilik kadara eskilere uzansa da her hayvanda ayn\u0131 oranda g\u00f6r\u00fclmez. Mesela fillerde veya t\u00fcys\u00fcz k\u00f6stebek farelerinde m\u00fcthi\u015f nadirdir. Yaban gelinci\u011fi ve k\u00f6pek gibi kimi hayvanlar ise al\u0131\u015f\u0131lmad\u0131k derecede y\u00fcksek oranlarda kansere yakalan\u0131r. Peki neden? 1977\u2019de \u0130ngiliz epidemiyoloji uzman\u0131 Richard Peto v\u00fccudu b\u00fcy\u00fck ve ya\u015fam s\u00fcresi uzun hayvanlar\u0131n di\u011ferlerine g\u00f6re daha fazla h\u00fccre b\u00f6l\u00fcnmesine u\u011frad\u0131\u011f\u0131n\u0131, […]<\/p>\n","protected":false},"author":184,"featured_media":32458,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[19,21,3729],"tags":[4562,444,4561,4560,4563],"class_list":["post-32464","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-bilim-gundemi","category-biyoloji","category-genetik","tag-filler","tag-kanser","tag-peto-ikilemi","tag-tp53-geni","tag-tuysuz-kostebek-fareleri"],"acf":[],"aioseo_notices":[],"aioseo_head":"\n\t\t\n\t\n\t\n\t\n\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t