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Priprava od majhnih molekul odvisnih dimerizacijskih sistemov na osnovi cepljenih proteinov
Rihtar, Erik (Author), Marinšek Logar, Romana (Mentor) More about this mentor... This link opens in a new window, Jerala, Roman (Co-mentor)

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Abstract
Od majhnih molekul odvisni dimerizacijski sistemi so pomembno orodje za preučevanje in zunanji nadzor številnih bioloških procesov. Do danes poznamo več takšnih sistemov (naprimer od rapamicina, od abscisinske kisline in od giberelinske kisline odvisne sisteme), vendar je to število še vedno majhno, kar omejuje uporabo. Poleg tega trenutno razpoložljivi od majhnih molekul odvisni dimerizacijski sistemi niso najprimernejši za uporabo v terapevtske namene, saj so nekatere molekule lahko za človeške celice toksične, ali pa sistemi izvirajo iz drugih organizmov in lahko izzovejo imunski odziv pri človeku. Tako smo se v magistrskem delu osredotočili na pripravo novih dimerizacijskih sistemov, ki so zasnovani na osnovi cepljenih človeških proteinov, sposobnih selektivne vezave majhne molekule. S takim pristopom smo pripravili od majhnih molekul odvisne dimerizacijske sisteme na osnovi cepljene kinaze Lyn, ki veže inhibitor dasatinib, ter enoverižnega variabilnega fragmenta protitelesa proti nikotinu. Pripravljene sisteme smo uporabili za od dasatiniba in nikotina odvisno aktivacijo transkripcije v sesalskih celicah v kombinaciji s sistemom CRISPR/dCas9. Verjamemo, da bodo od majhnih molekul odvisni dimerizacijski sistemi, pripravljeni v tem magistrskem delu, pripomogli k razširitvi nabora sintezno-bioloških orodij. Poleg tega je naša strategija univerzalna in uporabna za pripravo številnih novih dimerizacijskih sistemov na osnovi skoraj kateregakoli proteina, ki veže majhne molekule.

Language:Slovenian
Keywords:sintezna biologija, dimerizacijski sistemi, cepljeni proteini, kinaza Lyn, enoverižni variabilni fragment, CRISPR/dCas9 sistem
Work type:Master's thesis/paper (mb22)
Tipology:2.09 - Master's Thesis
Organization:BF - Biotechnical Faculty
Year:2019
Publisher:[E. Rihtar]
UDC:577.2.088:577.112
COBISS.SI-ID:5094776 Link is opened in a new window
Views:118
Downloads:0
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Secondary language

Language:English
Title:Engineering novel chemically-induced dimerization systems based on split proteins
Abstract:
Chemically-inducible dimerization systems are essential tools to interrogate and control biological systems. To date, the number of such systems is still limited, which impedes their broader application. Moreover, currently available chemically-inducible dimerization systems lack the properties desired for use in therapeutic applications as some small molecules can be toxic to human cells, while some proteins originate from other organisms and may trigger an immune response. To address these problems, we engeenered novel chemically-inducible dimerization systems based on split human proteins that selectively bind small molecules. Using this approach, we developed two efficient dimerization systems based on the split Lyn kinase, which binds the inhibitor dasatinib, as well as the single-chain variable fragment of an anti-nicotine antibody. We demonstrated the use of the designed chemically-inducible dimerization systems for dasatinib and nicotine inducible gene activation in mammalian cells in combination with CRISPR/dCas9 system. We believe that the chemically-inducible systems prepared in this MSc thesis will significantly expand the synthetic biology toolbox. Moreover, the engineering principle used in this MSc thesis is universal and could be used to create novel chemically-inducible systems based on almost any small molecule-binding protein.

Keywords:synthetic biology, dimerization systems, split proteins, Lyn kinase, single-chain variable fragment, CRISPR/dCas9 system

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