Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 47 for “"Synthetic Lethal"”.
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Identification of novel synthetic lethal interactions using multiplexed CRISPR-Cas9 screening
… The aim of this project is to identify novel synthetic lethal interactions within melanoma. Synthetic lethality describes a relationship between two genes, where loss of either of the pair is compatible with cellular viability, but simultaneous loss of both genes induces cell death. This …
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Expanding cancer therapy options through genome-scale identification of synthetic lethal paralogs
Synthetic lethal therapies have the potential to expand cancer treatment options. Synthetic lethality is a form of context-dependent gene essentiality in which dual inactivation of a gene pair leads to cell death but single-gene inactivation does not affect viability. When one synthetic lethal gene …
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Identifying Context-Specific Synthetic Lethal miRNA Inhibition in Non-Small Cell Lung Cancer
… gene regulators, to identify novel synthetic lethal miRNA inhibition:molecular mechanism interactions in NSCLC. I accomplished this by screening a panel of 13 NSCLC and immortalized normal lung epithelium (HBEC) cell lines in two phases to identify miRNA inhibitors with selective …
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Therapeutic Potential of Prmt5 and Mat2A As Synthetic Lethal Targets In Mtap-Deficient Gbm Tumors
… the influence of stromal infiltration on the synthetic lethal relationship between <em>MTAP</em>-deletion and PRMT5 inhibition, and the potential of co-treatment with putrescine and PRMT5 inhibitors to enhance this therapeutic approach.</p>
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Genome-wide CRISPR Screening in FBXW7-mutant Cells Uncovers Multiple Druggable Synthetic Lethal Interactions Involving Cell Cycle Control
… lines to identify genetic interactions that are synthetic lethal with common cancer-associated mutations in the Wnt signalling pathway and that could therefore represent new therapeutic targets. From this work we identified two novel druggable synthetic lethal interactions with the commonly …
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A Synthetic Lethal shRNA Screen and Genetic Proof of Concept Identifies RAC1 as a Novel Target to Disrupt Plexiform Neurofibroma Formation
Neurofibromatosis Type 1 (NF1) is a highly penetrant autosomal dominant genetic disorder where mutations in the tumor suppressor gene NF1 leads to decreased neurofibromin. The most debilitating manifestation is the presence of complex multilineage Schwann cell-derived plexiform neurofibromas (PN). …
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The IN4MER CRISPR/Cas12a Multiplex Knockout Platform and Its Applications
<p>Discovering synthetic lethal interactions between genes holds the key to uncovering cancer vulnerabilities, enabling the development of more effective drugs for patients. However, identifying these vulnerabilities in the complex genome of human, which comprises thousands of genes, poses a …
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Exploiting Chemogenetic and Genetic Interactions In Human Cells As An Avenue For New Therapeutic Opportunities
… both, genetic modifications involved in synthetic lethality as well as in resistance mechanisms. In addition to identifying known and novel chemogenetic interactions, I show that drugZ also provides insights into the experimental design of pooled CRISPR screens. The second part of this …
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Utilizing the IN4MER CRISPR/CAS12A Multiplex Knockout Platform To Investigate Synthetic Lethality in the Human Genome
… to achieve in the clinic. The concept of synthetic lethality has gained traction as a promising opportunity to discover novel cancer-specific vulnerabilities and therapeutic targets. Unfortunately, initial technologies for combinatorial genetic perturbation in mammalian cells suffer from …
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Identification of Oncogenic KRAS-Associated Vulnerabilities in Non-Small Cell Lung Cancer
… inhibitor has been developed. As an alternative, synthetic-lethal therapeutic opportunities are being pursued using large-scale, RNAi-based, functional genomics platforms. We first addressed two major challenges associated with RNAi-based primary synthetic-lethal screens; a prevalent miRNA-like …
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Application of CRISPR/Cas9 screening to study cancer drivers and to identify novel cancer vulnerabilities
… to treat these cancers is the exploitation of synthetic lethal interactions. Synthetic lethality describes an interaction between two genes, where loss of one gene alone does not affect viability but loss of both genes induces cell death. Inhibiting the synthetic lethal partner of a tumour …
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Genetic, Biochemical, and Electron Microscopic Analysis of Components Involved in Transcription Coupled mRNA Export
… pores. When I started my PhD work, I performed a synthetic lethal (sl) screen to investigate the role of Gle2 in mRNA export. Gle2 was a proposed to be an mRNA export factor. Thus, the aim has been to gain an understanding of the relationship between Gle2 and the Mex67-mediated mRNA export …
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Regulation of DNA replication and the replication initiator, DnaA, in Bacillus subtilis
… I identified an overinitiating, conditional synthetic lethal mutant of Bacillus subtilis. I isolated suppressors of this mutant and uncovered novel genes associated with DNA replication. These suppressors acted both at the steps of initiation and elongation to overcome the detrimental …
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Rational drug combinations to selectively target 9p21-deleted bladder cancer
… therapies. In this project we investigated the synthetic lethal vulnerabilities exposed by 9p21 loss in BLCA, the most common copy-number alteration in this tumor. Previous studies have investigated 9p21 loss across several cancer types and identified PRMT5 and MAT2A as synthetic lethal …
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Total Genomic Transcriptional Analysis of the Fatty Acid Degradation Regulon of Escherichia Coli
… by FadR. Double fabA(Ts), fadR mutants have a synthetic lethal phenotype, fabB(Ts), fadR strains were constructed and shown to behave in a similar fashion. Experiments involving chloramphenicol acetyl transferase fusions confirm that FadR positively regulates transcription of fabB as well.
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UNRAVELING THE MOLECULAR MECHANISM OF BRCA2-POLTETA INTERPLAY IN PREVENTING SSDNA GAP ACCUMULATION DURING DNA REPLICATION
… in the absence of homologous recombination. The synthetic lethal relationship between POLQ and BRCA1/2 has been well-established, but the underlying molecular mechanisms remain poorly understood. Here, we investigate the role of POLθ beyond alt-NHEJ and its interplay with BRCA2 during DNA …
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Induction of Synthetic Lethality In Mutant Kras Cells For Non-Small Cell Lung Cancers Chemoprevention and Therapy
… of TRAIL and Smac mimetic induced the synthetic lethal reaction specifically in the mutant-KRAS cells but not in normal lung cells and wild-type <em>KRAS</em> lung cancer cells. Therefore, a synthetic lethal interaction among TRAIL, Smac mimetic and <em>KRAS</em> mutations could be used …
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Genome-wide CRISPR Screens to Uncover Novel Therapeutic Targets in Wnt-β-catenin Driven Gastrointestinal Cancers
… of each RNF43 mutant PDAC line. We generated a synthetic human monoclonal antibody specific to FZD5, and found it effective in reducing the growth of RNF43 mutant pancreatic cancers in vitro and in orthotopic xenograft models. We next identified the homeobox transcription factor CDX2 as a …
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