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 19 of 19 for “"MBNL1"”.
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Unraveling the interactions between MBNL1 protein and its RNA targets
The muscleblind-like protein 1 (MBNL1) is an RNA binding protein with four conserved zinc fingers that plays an important role in the regulation of alterative splicing. It interacts with pre-mRNA and promotes the inclusion or exclusion of exons to form different mRNA transcripts. Besides its …
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Investigating the Role of Muscleblind-Like 1 in the Suppression of Breast Cancer Progression
… the RNA binding protein Muscleblind-like 1 (MBNL1) is identified as a novel suppressor of breast cancer metastasis. MBNL1 loss-of-function contributes to the pathogenesis of myotonic dystrophy, a human genetic disease, but has no reported role in tumorigenesis or cancer progression. In this …
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Co-regulation of the Smooth Muscle Cell Alternative Splicing Programme by the RNA-Binding Proteins RBPMS, RBFOX2, MBNL1, and QKI
… unclear. In this study, I investigated RBFOX2, MBNL1, and QKI as potential co-regulators of RBPMS in VSMC AS regulation. RBFOX2 was identified as a key candidate due to enrichment of its GCAUG binding motifs around RBPMS-regulated exons in positions suggesting cooperative regulation. MBNL1 was …
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Advances in myotonic dystrophy type 1 drug discovery through design of novel ligands and mechanism establishment
… that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUGexp RNA is a validated drug target for this currently untreatable disease. Herein, we describe the development of a bioactive small molecule (Chapter 2) and a small library of dimeric ligands …
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Alternative isoform regulation in myotonic dystrophy
… and cells depleted of MBNLs, we found that MBNL1 and MBNL2 co-regulate hundreds of redundant targets. MBNL1 UV cross-linking and immunoprecipitation, followed by sequencing (CLIPseq), was used to identify the in vivo transcriptome-wide binding locations of MBNL1, and facilitated the …
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Developing potential drugs for the treatment of myotonic dystrophy: from rational design to lead development
… known that the alternative splicing regulator, MBNL1, is sequestered by two types of abnormally long RNAs. Specifically there are the tri- and tetra-nucleotide repeats, CUG and CCUG, in DM1 and DM2, respectively. This key discovery inspired the development of ligands that inhibit MBNL1-RNA …
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Identification and investigation of RNA-binding ligands
… gene that sequesters a key splicing regulator, MBNL1, preventing normal modulation of alternative splicing of a variety of genes. Targeting these repeats with small molecules could block the sequestration of MBNL1 and restore normal splicing levels, alleviating the pathogenesis of the disease. …
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Understanding the pathogenesis of myotonic dystrophy type 1
… which mimicked the nuclear foci formation and MBNL1 co-localisation seen in patient cells. Expression of exogenous MBNL1/GFP fusion protein in this model resulted in an increase in the size of foci, indicating that MBNL1 protein is limiting within the cell, and may possibly play a protective …
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Approaches to the assembly of potent therapeutic agents for the treatment of myotonic dystrophy
… CTG repeat, whose RNA transcript sequesters the MBNL1 protein into nuclear foci, leading to the misregulation of various pre-mRNAs. Based on a published x-ray structure of a r(CUG)6 hairpin, a benzamidinium ligand was rationally designed and found to selectively bind rCUG repeats and inhibit the …
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Understanding regulation of mRNA by RNA binding proteins
… splicing factors RBFOX2, MBNL1 and CELF1/CUGBP1. For each factor, the canonical motifs are recovered as well as additional near-optimal binding motifs. RNA secondary structure inhibits binding of RBFOX2 and CELF1, while MBNL1 favors unpaired Us but tolerates C/G pairing in …
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RNA recognition: controlling RNA-protein complexes with small molecules
… the Interaction of Pathogenic RNAs with the MBNL1 Protein and Complex Inhibition by Small Molecules PART I. RNA plays important and versatile roles in gene expression by both carrying and regulating the information used to direct protein synthesis. Therefore, small molecules able to bind to …
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Design, synthesis, and biological activities of small molecules that target myotonic dystrophy
… focused on agents targeting the CUGexp/CCUGexp -MBNL1 interaction. This dissertation focuses on the development of rationally designed small molecules that target CUGexp and CCUGexp, including their synthesis and studies of their biological activity. The background of DM with a focus on its …
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Development of therapeutic agents for myotonic dystrophy type 1
… inhibiting the interaction between r(CUG)exp and MBNL1 proteins, because it is estimated that over 80% of DM1 splicing defects are related to MBNL1 sequestration. This dissertation focuses on the development of rationally designed small molecules that can function as potential therapeutic agents, …
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Lead compound discovery for myotonic dystrophy
… mRNA which mislocalize splicing factors such as MBNL1 and lead to missplicing in the cell. One therapeutic strategy is to target such mutant mRNA with small molecules to prevent the sequestration of splicing factors which will prevent the multiple missplicing events in the cell and rescue the …
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Development of enforced stacked intercalators that target trinucleotide repeat mismatches in DNA
… of key pre-mRNA splicing proteins, such as MBNL1. Indeed, since we reported our first ligand JFA in 2009, our group has been at the forefront in discovering ligands that specifically bind U–U mismatches and can potentially be used as therapeutics. More recently, we have started to focus our …
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Identification of RBPMS as a smooth muscle master splicing regulator via association of its gene with super-enhancers
… splicing and post-transcriptional regulators (MBNL1, MBNL2 and LSM14B) as well as the key SMC transcription factor Myocardin. Structure-function analyses revealed that the two major RBPMS isoforms (RBPMS-A and B) have differential activity, and that dimerization and RBPMS C- terminus are …
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Global analysis of mRNA decay rates and RNA-binding specificity reveals novel roles for CUGBP1 and PARN deadenylase in muscle cells
… function of the RNA-binding proteins CUGBP1 and MBNL1 are disrupted, resulting in altered mRNA metabolism at the levels of splicing and translation. Intriguingly, despite strong evidence for CUGBP1 being a regulator of mRNA turnover in humans and other organisms, the possibility that defects in …
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Development of polynorbornenes and polypeptides as versatile functional biomaterials
… disperse ribonuclear foci caused by r(CUG)n-MBNL1 complex, and could fully reverse the mis-splicing of Insulin receptor (IR) mRNAs in the model cells. In addition, potentially due to the polymer-mediated catalytic degradation, r(CUG)n level in the model cells could be greatly reduce by low …
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Advances in high-throughput screening: better compounds, novel targets, enhanced sensors
High throughput screening (HTS) is the dominant force in modern drug discovery. Through the evaluation of large structure collections, novel drug leads can be rapidly assessed for modulation of medicinally-relevant biological targets. This occurs through the interplay of three intrinsically linked …