Study of the segregation mechanism of the Bovine Papillomavirus Type 1
Date
2010-08-16
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Abstract
Papilloomiviirused (PV) on DNA genoomiga viirused, mis nakatavad epiteelkoe rakke. PV-te peremeestering on väga lai. Lisaks lindudele ja roomajatele on kirjeldatud enam kui 100 erinevat tüüpi PV-i, mis nakatavad inimesi (HPV- human papillomavirus). Väga suure tõenäosusega mingil elu etapil iga inimene nakatub ühe või enama HPV-ga. Nendele viirustele on iseloomulik pikaajaline vaikoleku võime. Seega, HPV võib inimese rakkudes püsida aastaid põhjustamata ühtegi haigust. Perioodiliselt siiski võivad HPV-d nakatunud kudedes põhjustada healoomulisi vohandeid- soolatüükaid ja kondüloome. Kuid lisaks soolatüügastele ja kondüloomidele võivad mõned pahaloomulised HPV-d põhjustada ka emakakaela kasvajat, mis üle maailma põhjustavad ligikaudu 250000 surmajuhtu igal aastal. See fakt muudab PV-d meditsiiniliselt olulisteks objektideks.
Kaua oli saladuseks, kuidas PV-d suudavad aastaid rakkudes püsida ja rakkust rakku liikuda. Nüüdseks on teada, et viiruse genoomid on viiruselise valgu E2 vahendusel seotud peremeesraku kromosoomidele ning kui toimub kromosoomide jagunemine peremeesraku pooldumise ajal, siis viiruse genoomid nö. transporditakse uude tütarrakku koos peremehe kromosoomidega. Oma doktoritöös olengi keskendunud viirusvalgu E2 poolt vahendatud rakust rakku liikumise mehhanismi uurimisele. Meil õnnestus konstrueerida kahest viirusest hübriidsed DNA molekulid, mis E2 valgu juuresolekul olid võimelised rakkudes pikk aega säilima. See töö näitas, et PV vaikolekut tagav element on funktsionaalne ka koos teistest viirustest pärit elementidega. Praeguseks on selle töö tulemused ka patenteeritud ning leidnud tööstuslikku kasutamist. Väga paljud maailmas kasutatavad ravimid on valgud, kuid valkude tootmine on aeganõudev ja kulukas. Meie poolt patenteeritud tehnoloogia kasutab ära PV vaikoleku elementi, et muuta valgutootmine kiiremaks ja ka odavamaks. Tehnoloogia arendamine toimub praeguseks firmas Icosagen Cell Factory OÜ ning mitmed kuulsad ravimifirmad nagu Bayer Healthcare, Novartis, Wyeth, GE Healthcare on omandanud selle tehnoloogia litsentsi. Lisaks rakenduslikule poolele, uurisin oma doktoritöös rakulise valgu Brd4 mõju E2 valgu funktsioonidele ning püüdsin kaardistada need E2-e osad, mis on vaikoleku tagamisel olulised.
Papillomaviruses (PVs) are diverse group DNA viruses that have been found in more than 20 different mammalian species, as well as in birds and reptiles. PVs have their life cycle exclusively in body surface tissues such as the skin, or the mucosal surfaces of the genitals, anus, and mouth. Visible symptoms of PV infection are benign tumors- warts, papillomas, condylomas. To date, more then 100 human papillomavirus types (HPV) has been isolated. Many PV occur preferentially in a latent life cycle without causing any visible symptoms. However, some HPVs are responsible for causing cervical cancer, which is source for 250000 deaths every year. It has been longstanding challenge to discover the mechanism for PV stable maintenance- how PVs are maintained in the cells and how they are moving from cell to cell? Nowadays it is known that PV encoded protein E2 tethers viral genomes to the host chromatin. This robust tethering mechanism ensures that viral genomes are more evenly distributed between daughter cells, thus ensuring genome maintenance in dividing cells and persistent viral infection. In current thesis I have focused to E2 mediated segregation process. We succeeded to construct hybrid DNA molecules, which in the presence of E2 protein are stably maintained. We were first to demonstrate that PV stable maintenance element is functional in hetereologues configuration. These findings have been patented and already used in biotechnology. Modern biotechnology and pharmaceutical industry need lots of amounts of pure proteins for screenings in drug development. In addition, many drugs currently on market contain protein component. However, protein production is very time consuming and usually very expensive. Our patented technology enables shorten the time period for protein production and also makes it more inexpensive. Currently the technology is further developed by company Icosagne Cell Factory OÜ and it has already been licensed for such well-known pharmaceutical companies as Bayer Healthcare, Novartis, Wyeth and GE Healthcare. In addition, I studied cellular protein Brd4 influences to E2 protein functions and I characterized E2 domains that are required in stable maintenance process.
Papillomaviruses (PVs) are diverse group DNA viruses that have been found in more than 20 different mammalian species, as well as in birds and reptiles. PVs have their life cycle exclusively in body surface tissues such as the skin, or the mucosal surfaces of the genitals, anus, and mouth. Visible symptoms of PV infection are benign tumors- warts, papillomas, condylomas. To date, more then 100 human papillomavirus types (HPV) has been isolated. Many PV occur preferentially in a latent life cycle without causing any visible symptoms. However, some HPVs are responsible for causing cervical cancer, which is source for 250000 deaths every year. It has been longstanding challenge to discover the mechanism for PV stable maintenance- how PVs are maintained in the cells and how they are moving from cell to cell? Nowadays it is known that PV encoded protein E2 tethers viral genomes to the host chromatin. This robust tethering mechanism ensures that viral genomes are more evenly distributed between daughter cells, thus ensuring genome maintenance in dividing cells and persistent viral infection. In current thesis I have focused to E2 mediated segregation process. We succeeded to construct hybrid DNA molecules, which in the presence of E2 protein are stably maintained. We were first to demonstrate that PV stable maintenance element is functional in hetereologues configuration. These findings have been patented and already used in biotechnology. Modern biotechnology and pharmaceutical industry need lots of amounts of pure proteins for screenings in drug development. In addition, many drugs currently on market contain protein component. However, protein production is very time consuming and usually very expensive. Our patented technology enables shorten the time period for protein production and also makes it more inexpensive. Currently the technology is further developed by company Icosagne Cell Factory OÜ and it has already been licensed for such well-known pharmaceutical companies as Bayer Healthcare, Novartis, Wyeth and GE Healthcare. In addition, I studied cellular protein Brd4 influences to E2 protein functions and I characterized E2 domains that are required in stable maintenance process.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
doktoritööd, bioloogia, Papilloomiviirused