Discovering genetic factors that regulatecancer therapy resistance using novel yeastbased complex trait analysis approaches
Başlık çevirisi mevcut değil.
- Tez No: 645703
- Danışmanlar: DR. STEVEN S. FOSTER
- Tez Türü: Yüksek Lisans
- Konular: Moleküler Tıp, Tıbbi Biyoloji, Molecular Medicine, Medical Biology
- Anahtar Kelimeler: Chemotherapy, doxorubicin, cisplatin, drug resistance, hormesis, caloric restriction, QTL analysis, soft tissue sarcoma, Saccromyces cerevisiae
- Yıl: 2017
- Dil: İngilizce
- Üniversite: University of Leicester
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 83
Özet
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Özet (Çeviri)
Cancer cells acquire new phenotypes, such as therapy resistance as the disease develops and progresses. Soft tissue sarcomas are heterogeneous and aggressive type of cancers that demonstrate a higher rate of drug resistance. The aim of this project was to identify novel genes involved in potential drug resistance mechanisms induced by clinically relevant chemotherapeutic agents; doxorubicin and cisplatin. These drugs as in combination, and in low doses were tested. To discover candidate genes we used a very high-resolution yeastbased quantitative analysis approach. Our system uses multi-parent F12 advanced-intercross line progeny possessing extensive natural genetic and phenotypic variation. Isolates from worldwide locations were used to obtain genetic diversity. By using high throughput growth phenotyping approach, 192 segregants were arrayed to be tested for 68 hours growth with optimised doses drugs to detect variation motif based on segregants drug sensitivities. Growth phenotype data used to perform r/QTL (Quantitave trait loci) analysis to discover loci influencing the drug resistance mechanism. In total, 63 genes found (by using Saccromyces genome database, yeastmine and humanmine) within the loci, 49 of which conserved. Most of the genes function in the cell cycle and DNA damage response. A novel gene, CST26 with 5 human homologs identified and tested for a role. CDT26 deletion strains exhibited increased sensitivity to doxorubicin, possibly due to disorganisation of the phospholipid structures. Hormesis experiments revealed that continuous low dose of doxorubicin treated yeasts induced a persistence hormetic response to high dose. Caloric restriction increased resistance to doxorubicin and cisplatin but hormetic responses were temporary. Uncovering possible drug resistance mechanisms will shed light on poorly understood cellular responses to chemotherapeutic agents. This will benefit drug discovery and overcome drug resistance ultimately develop better treatments and prevention for soft tissue sarcomas and other diseases.
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