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Fuzija adapterskega proteina MYD88 s CD19 CAR za večjo učinkovitost CAR-T celične imunoterapije raka.
ID Pantović, Jelica (Author), ID Jerala, Roman (Mentor) More about this mentor... This link opens in a new window

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Abstract
Imunoterapija raka s celicami CAR-T predstavlja uspešno alternativo klasičnemu zdravljenju raka. Uspehe dosega predvsem pri hematoloških oblikah raka, kot so različni limfomi in akutna limfoblastna levkemija, medtem ko so solidni tumorji še vedno izziv. K slabšemu učinku terapije doprinesejo predvsem T-celična izčrpanost in senescenca ter inhibitorno tumorsko mikrookolje solidnih tumorjev, zato se išče rešitve v smeri dodajanja domen himernemu antigenskemu receptorju, ki bi vplivale na učinkovitost terapije- tako na večjo aktivnost celic kot tudi na njihovo daljšo obstojnost v telesu, pri čemer ne bi poslabšali lastnosti imunoterapije CAR-T. Pri tem si pomagamo z orodji sintezne biologije. Naš cilj je bil ustvariti receptor CD19 CAR, ki bi poleg klasičnih elementov vseboval še domene izhajajoče iz adapterskega proteina MyD88, ki igra pomembno vlogo v naravni imunosti. Z različnimi metodami smo dobili vpogled v vpliv tako spremenjenega receptorja na aktivnost modificiranih celic ob ustrezni stimulaciji, na izražanje receptorja in na izražanje inhibitorja ključnega transkripcijskega faktorja NF-κB, IκBα. Opazili smo večjo aktivnost, izražanje receptorja na membrani in različno izražanje IκBα glede na čas stimulacije.

Language:Slovenian
Keywords:imunoterapija raka, CAR, MyD88, sintezna biologija
Work type:Master's thesis/paper
Typology:2.09 - Master's Thesis
Organization:BF - Biotechnical Faculty
Place of publishing:Ljubljana
Publisher:[J. Pantović]
Year:2021
PID:20.500.12556/RUL-128641 This link opens in a new window
UDC:606:616-006.6:602.68(043.2)
COBISS.SI-ID:72148995 This link opens in a new window
Publication date in RUL:22.07.2021
Views:893
Downloads:32
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Secondary language

Language:English
Title:MYD88 adapter protein fusion with CD19 CAR for more efficient CAR-T cell immunotherapy for cancer
Abstract:
CAR-T immunotherapy for cancer represents a successful alternative to classic cancer treatment. It is very successful with the haematological malignancies such as different lymphomas and acute lymphoblastic leukemia, however not so much with solid tumors, which still represent a challenge. Contributors that lower response rates are mainly T-cell exhaustion, senescence and inhibitory tumor microenvironment. That is why researchers are looking for a solution by adding domains to chimeric antigen receptor which would affect efficiency of the therapy- meaning higher activity and longer persistence, where negative aspects of the CAR-T immunotherapy would not be increased. To modulate CAR-T immunotherapy synthetic biology tools are used. Our aim was to create CD19 CAR receptor which would express domains from MyD88 adapter protein, a key mediator of innate immunity, in addition to traditional receptor elements. By using different methods we got an insight into the effect of such a receptor on activity of modified cells when stimulated correctly. We also got an insight into expression of receptor and expression of inhibitor of the key transcription factors NF-κB, IκBα. We observed higher activity, receptor expression on the cell membrane and different IκBα expression at different stimulation time.

Keywords:cancer immunotherapy, CAR, MyD88, synthetic biology

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