subject:(Nucleic Acids Nucleotides AND Nucleosides)

Boston College

1. Theile, Christopher Stone. Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides.

Degree: PhD, Chemistry, 2012, Boston College

URL: http://dlib.bc.edu/islandora/object/bc-ir:101931

► Nucleic acids are responsible for maintaining the biological information responsible for the activities of all known living organisms. Research of nucleic acids provides opportunities to… (more)

Subjects/Keywords: cyclonucleoside; DNA; Nucleic Acids; Nucleosides; nucleotides; RNA

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APA (6^th Edition):

Theile, C. S. (2012). Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides. (Doctoral Dissertation). Boston College. Retrieved from http://dlib.bc.edu/islandora/object/bc-ir:101931

Chicago Manual of Style (16^th Edition):

Theile, Christopher Stone. “Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides.” 2012. Doctoral Dissertation, Boston College. Accessed March 08, 2021. http://dlib.bc.edu/islandora/object/bc-ir:101931.

MLA Handbook (7^th Edition):

Theile, Christopher Stone. “Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides.” 2012. Web. 08 Mar 2021.

Vancouver:

Theile CS. Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides. [Internet] [Doctoral dissertation]. Boston College; 2012. [cited 2021 Mar 08]. Available from: http://dlib.bc.edu/islandora/object/bc-ir:101931.

Council of Science Editors:

Theile CS. Synthesis of Cyclo, Ring Expanded, and Backbone Extended Nucleosides. [Doctoral Dissertation]. Boston College; 2012. Available from: http://dlib.bc.edu/islandora/object/bc-ir:101931

Florida International University

2. de Cabrera, Maria E. Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides.

Degree: PhD, Chemistry, 2019, Florida International University

URL: https://digitalcommons.fiu.edu/etd/4229 ; FIDC007805

► Gemcitabine is a potent anticancer cytidine analogue used to treat solid tumors. Its efficacy is diminished by rapid deamination to a toxic uridine derivative… (more)

▼ Gemcitabine is a potent anticancer cytidine analogue used to treat solid tumors. Its efficacy is diminished by rapid deamination to a toxic uridine derivative by cytidine deaminase. To overcome this limitation and add radioactive nuclei (¹⁸F or ⁶⁸Ga) for PET imaging, I synthesized two 4-N-alkylgemcitabine analogues i) bearing β-keto tosylate moiety for subsequent ¹⁸F-fluorination and ii) having SCN-Bn-NOTA chelator to complex ⁶⁸Ga. The first was synthesized by replacement of tosylamide in 4-N-tosylgemcitabine with 1-amino-10-undecene, followed by elaboration of terminal alkene through dihydroxylation, regioselective tosylation and oxidation. Subsequent fluorination using KF in presence of 18-Crown-6 at 75°C for 1 hr gave 4-N-alkylgemcitabine fluoromethyl ketone. The second was synthesized by analogous replacement of tosylamide with N-Boc-1,3-propanediamine, followed by deprotection with TFA. The reactive terminal amine was condensed with SCN-Bn-NOTA, giving 4-N-alkylgemcitabine-SCN-Bn-NOTA ligand, which efficiently complexed Ga or ⁶⁸Ga for in vivo PET studies in rats. Clofarabine is a highly effective chemotherapeutic adenosine analogue used for treatment of acute lymphoblastic leukemia. Clofarabine undergoes rate limiting phosphorylation from its 5'-monophosphate to 5'-diphosphate by purine monophosphate kinase, and possible dephosphorylation of its respective 5'-monophosphate by 5'-nucleotidases. Synthesis of clofarabine diphosphate prodrugs, and potentially their ¹⁸F-radiolabeled analogues, were undertaken to overcome these limitations. Successful synthesis of model adenosine diphosphate prodrug, by coupling adenosine monophosphate with bis(benzoyloxybenzyl) phosphoramidite in presence of 5-phenyl-1-H-tetrazole activator was achieved. The aminyl radical generated from azide moiety in 3'-azido-3'-deoxythymidine (3'-AZT) or 5-azidomethyl-2'-deoxyuridine (AmdU), upon addition of radiation-produced electrons, is thought to be the source of their radiosensitizing effects. Herein, I report synthesis of azido-modified purine and pyrimidine analogues for EPR study of formation of reactive aminyl radical in guanine, adenine and cytidine bases. The EPR studies of electron addition to 2-azidoguanosine (i.e. 2-azidoinsoine), protected 4-azidocytidine and 4-tetrazolocytidine analogues clearly establish that the position of the azide in base moiety dictates reactivity. The azide directly attached to nucleobases at ortho/para position to ring nitrogens produce stable RN₃•^- that does not rapidly convert to aminyl radical, except in the excited state. Hence, these did not display much radiosensitizing effects in in vivo biological studies in MDA-MB-231, MCF7 and U87 cell lines. Advisors/Committee Members: Stanislaw F. Wnuk, Raphael Raptis, Kathleen Rein, M. Alejandro Barbieri, Jose Almirall.

Subjects/Keywords: Nucleosides; Prodrugs; PET Imaging; 18-Fluorine; 68-Gallium; Nucleotides; Radicals; Azides; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

de Cabrera, M. E. (2019). Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides. (Doctoral Dissertation). Florida International University. Retrieved from https://digitalcommons.fiu.edu/etd/4229 ; FIDC007805

Chicago Manual of Style (16^th Edition):

de Cabrera, Maria E. “Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides.” 2019. Doctoral Dissertation, Florida International University. Accessed March 08, 2021. https://digitalcommons.fiu.edu/etd/4229 ; FIDC007805.

MLA Handbook (7^th Edition):

de Cabrera, Maria E. “Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides.” 2019. Web. 08 Mar 2021.

Vancouver:

de Cabrera ME. Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides. [Internet] [Doctoral dissertation]. Florida International University; 2019. [cited 2021 Mar 08]. Available from: https://digitalcommons.fiu.edu/etd/4229 ; FIDC007805.

Council of Science Editors:

de Cabrera ME. Nucleoside Analogues for Positron Emission Tomography Imaging and to Study Radiation Mediated Generation of Radicals from Azides. [Doctoral Dissertation]. Florida International University; 2019. Available from: https://digitalcommons.fiu.edu/etd/4229 ; FIDC007805

3. Lin, Annie. Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs.

Degree: 2019, James Madison University

URL: https://commons.lib.jmu.edu/honors201019/694

► Antisense oligonucleotides (ASO) are single-stranded deoxyribonucleic acids that bind to mRNA to inhibit the synthesis of proteins that have been associated with the central mechanisms… (more)

Subjects/Keywords: Antisense Oligonucleotides; Analogs; Cyclic Monomers; Oligomers; Ring-Opening; DNA/RNA; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Lin, A. (2019). Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs. (Masters Thesis). James Madison University. Retrieved from https://commons.lib.jmu.edu/honors201019/694

Chicago Manual of Style (16^th Edition):

Lin, Annie. “Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs.” 2019. Masters Thesis, James Madison University. Accessed March 08, 2021. https://commons.lib.jmu.edu/honors201019/694.

MLA Handbook (7^th Edition):

Lin, Annie. “Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs.” 2019. Web. 08 Mar 2021.

Vancouver:

Lin A. Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs. [Internet] [Masters thesis]. James Madison University; 2019. [cited 2021 Mar 08]. Available from: https://commons.lib.jmu.edu/honors201019/694.

Council of Science Editors:

Lin A. Overcoming degradation: A novel synthetic strategy for antisense oligonucleotide analogs. [Masters Thesis]. James Madison University; 2019. Available from: https://commons.lib.jmu.edu/honors201019/694

Northeastern University

4. LaBeaume, Paul. Designed small molecule approaches to macromolecular targets.

Degree: PhD, Department of Chemistry and Chemical Biology, 2010, Northeastern University

URL: http://hdl.handle.net/2047/d20000879

► As researchers continue to unveil the role between structure and function, the potential use of nucleic acids as a therapeutic target grows.1 Nucleic acids can… (more)

▼ As researchers continue to unveil the role between structure and function, the potential use of nucleic acids as a therapeutic target grows.1 Nucleic acids can have richly diverse structures2 and are of general biological significance3 being suggested as binding motifs for regulatory proteins involved with viral replication, including the TAR region of HIV-1.4 Additionally, the etiology of at least 12 human neurodegenerative genetic diseases has been attributed to genetic variations in the lengths of triplet repeats in genomic DNA. The unstable expansion of triplet repeats has been attributed to reiterative synthesis due to slippage and bulge formation in the newly formed DNA strand.5 As such, compounds capable of binding to bulges could have significant therapeutic potential. Despite these obvious ramifications, few previous attempts have been made to prepare compounds with affinity for bulged sequences. The most promising bulgespecific agent discovered to date originated from work on the enediyne natural product NCSchrom.6 Based on this finding we have designed libraries of compounds and have achieved nanomolar affinity for specific bulged sequences.7 A schematic route towards the next generation of synthetic bulge binders has been developed. In addition, we have developed synthetic routes to a series of photoactivated enediyne pharmacophores which target duplex DNA. The designed agents were functionalized through PEGylation and derivatized to improve water solubility. These enediynes undergo photo activation to produce cytotoxic diradicals on demand.8; Despite an increased interest in nucleic acid targeting, proteins still remain a focus for small molecule drug design. The discovery of the cannabinoid 1 (CB1) receptor in the 1990's bolstered an interest in the development of novel ligans capable of antagonizing the receptor.9 Symmetric and asymmetric schemes based off the Sanofi-Aventis lead compound AVE16254 have been developed. A library of over 40 novel CB1selective receptor ligands has been constructed with affinity in the low nanomolar range.; In another area of work, new methods for the rapid incorporation of radio labels using microwave chemistry has been developed. The introduction of fluorine into drugs is not only important to medicinal chemistry for its physiochemical and metabolic impact,10 but also for its use as an imaging agent using positron emission tomography (PET).11 Microwave accelerate fluorodenitration12 and Negishi-fluoroalkylation reactions are described.; References:; 1. (a) Borman, S. Chem. Eng. News 2009, 87, 63. (b) Gallego, J.; Varani, G. Acc. Chem. Res. 2001, 34, 843. (c) Sucheck, S. J.; Wong, C.-H. Curr. Op. Chem. Bio. 2000, 4, 678.; 2. Sanger, W. Principles of Nucleic Acid Structure, Springer, New York, 1994.; 3. (a)Turner, D. H. Curr. Opin. Struct. Biol. 1992, 2, 334. (b) Chastain, M.; Tinoco, I. In Progress in Nucleic Acid Research and Molecular Biology, Cohn, W. E.; Moldave, D.eds., Academic, New York, 1991, 41, 131-177.; 4. (a) Lilley, D. M. S. Proc. Natl. Acad.…

Subjects/Keywords: Cannabinoid; DNA; Enediyne; Microwave; Radiolabels; RNA; Bioconjugates; Nucleic acids; Chemotherapy; Biochemistry; Macromolecular Substances; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

LaBeaume, P. (2010). Designed small molecule approaches to macromolecular targets. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/d20000879

Chicago Manual of Style (16^th Edition):

LaBeaume, Paul. “Designed small molecule approaches to macromolecular targets.” 2010. Doctoral Dissertation, Northeastern University. Accessed March 08, 2021. http://hdl.handle.net/2047/d20000879.

MLA Handbook (7^th Edition):

LaBeaume, Paul. “Designed small molecule approaches to macromolecular targets.” 2010. Web. 08 Mar 2021.

Vancouver:

LaBeaume P. Designed small molecule approaches to macromolecular targets. [Internet] [Doctoral dissertation]. Northeastern University; 2010. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/2047/d20000879.

Council of Science Editors:

LaBeaume P. Designed small molecule approaches to macromolecular targets. [Doctoral Dissertation]. Northeastern University; 2010. Available from: http://hdl.handle.net/2047/d20000879

5. Ghosh, Shubhendu. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.

Degree: Molecular Genetics and Microbiology, Microbiology and Physiological Systems, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/454

► The proper workings of an organism rely on the accurate expression of genes throughout its lifetime. An important determinant for protein production is the… (more)

▼ The proper workings of an organism rely on the accurate expression of genes throughout its lifetime. An important determinant for protein production is the availability of template mRNA molecules, the net effect of which is governed by their rates of synthesis vs. their rates of degradation. Normal mRNAs are proposed to be relatively stable in the cytoplasm while present in a protective, circularized conformation – the closed loop – through eIF4G-bridged interactions with 3’-bound poly(A) binding protein (Pab1p) and 5’-bound eIF4E. Introduction of a premature nonsense codon into an otherwise normal mRNA results in its rapid destabilization in cells, suggesting that not all stop codons behave the same, and events at premature termination events that lead to accelerated degradation of nonsense-containing mRNAs likely differ from those at normal termination, in which normal decay rates are maintained. The enhanced degradation observed for nonsense-containing mRNAs occurs through an evolutionarily conserved pathway involving the products of the UPF1, UPF2/NMD2, and UPF3 genes, the precise biochemical roles of which have remained elusive. We have developed a yeast cell-free translation system that allows us to assay biochemical events occurring at premature termination codons, compare them to those occurring at normal terminators, and study the role of Upf1p in these events. We find that premature termination is an inefficient process compared to normal termination and that one outcome of termination at a premature termination codon (PTC) is reinitiation at a nearby start codon. This in vitro post-termination reinitiation phenotype is dependent on the presence of Upf1p, a finding we have recapitulated in vivo. We also developed biochemical assays to define a role for Upf1p in translation following premature termination in vitro and find that Upf1p is involved in post-termination ribosome dissociation and reutilization. Supporting this idea are our findings that Upf1p predominantly cosediments with purified 40S ribosomal subunits. Finally, using our in vitro translation/toeprinting system, we have further characterized events leading to the formation of the mRNA closed loop structure and find that two states of the closed loop exist. The first requires the preinitiation 48S complex and includes Pab1p, eIF4G, eIF4E, and eIF3, whereas the second is formed after 60S joining and additionally requires the translation termination factors eRF1 and eRF3. Advisors/Committee Members: Dr. Allan Jacobson.

Subjects/Keywords: RNA; Messenger; RNA Stability; Protein Biosynthesis; Amino Acids, Peptides, and Proteins; Cells; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Ghosh, S. (2010). Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/454

Chicago Manual of Style (16^th Edition):

Ghosh, Shubhendu. “Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/454.

MLA Handbook (7^th Edition):

Ghosh, Shubhendu. “Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.” 2010. Web. 08 Mar 2021.

Vancouver:

Ghosh S. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/454.

Council of Science Editors:

Ghosh S. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/454

Wilfrid Laurier University

6. Rice, Kyle. Characterization of the Microbial Phosphonate-Activating PntC Enzymes.

Degree: 2019, Wilfrid Laurier University

URL: https://scholars.wlu.ca/etd/2163

► New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role… (more)

▼ New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role in maintaining health motivates discovery of species-specific antibiotics that minimally disrupt our native bacterial communities. Small molecule modifications to bacterial cell surfaces represent a potentially rich source of new targets for next generation antibiotics, as these molecules mediate virulence and evasion of the host immune response. Phosphocholine (PCho) is a rare cell surface modification that contributes to virulence, and modifications with phosphonates like 2-aminoethylphosphonate (AEP) are even more unusual and therefore provide opportunities for species- and pathway-specific targeting. Cytidylyltransferase enzymes are required to activate these unique substrates. The cytidylyltransferase LicC was previously known to activate PCho through addition of a cytidine monophosphate (CMP) moiety, and here we demonstrate that the homologous protein that we have termed PntC activates AEP. PntC homologs and resulting cell-surface phosphonate modifications have been identified across diverse phyla of bacteria. Among these bacterial species are the known pathogens Atopobium rimae, Olsenella uli, Treponema denticola, and Streptococcus pneumoniae. NMR analysis and continuous spectrophotometric assays were performed to compare LicC from S. pneumoniae (Spn-LicC) to PntCs from the Gram positive A. rimae (Ari-PntC) and Gram negative T. denticola (Tde-PntC). The results demonstrated that: (i) PntC enzymes generate a previously unreported compound CMP-AEP; (ii) PntCs exhibit specificity towards CTP and Mg2+; (iii) PntCs possess >400-fold preference for AEP over PCho, while LicC exhibits a 200-fold preference for PCho over AEP; and (iv) LicC is capable of accepting a range of larger substrates. These findings have provided insight into the activity and versatility of these proteins to utilize uncommon molecular substrates, setting the stage for the development of molecular probes and effective protein-specific inhibitors designed to halt the overall phosphonate-tailoring pathway which could ultimately disrupt the ability of the pathogen to confer virulence in a host.

Subjects/Keywords: Nucleotidyltransferase; Enzyme Kinetics; Proteins; Amino Acids, Peptides, and Proteins; Biochemistry; Enzymes and Coenzymes; Nucleic Acids, Nucleotides, and Nucleosides; Other Chemistry

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APA (6^th Edition):

Rice, K. (2019). Characterization of the Microbial Phosphonate-Activating PntC Enzymes. (Thesis). Wilfrid Laurier University. Retrieved from https://scholars.wlu.ca/etd/2163

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rice, Kyle. “Characterization of the Microbial Phosphonate-Activating PntC Enzymes.” 2019. Thesis, Wilfrid Laurier University. Accessed March 08, 2021. https://scholars.wlu.ca/etd/2163.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rice, Kyle. “Characterization of the Microbial Phosphonate-Activating PntC Enzymes.” 2019. Web. 08 Mar 2021.

Vancouver:

Rice K. Characterization of the Microbial Phosphonate-Activating PntC Enzymes. [Internet] [Thesis]. Wilfrid Laurier University; 2019. [cited 2021 Mar 08]. Available from: https://scholars.wlu.ca/etd/2163.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rice K. Characterization of the Microbial Phosphonate-Activating PntC Enzymes. [Thesis]. Wilfrid Laurier University; 2019. Available from: https://scholars.wlu.ca/etd/2163

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Lin, Ling. Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation.

Degree: Interdisciplinary Graduate Program, Molecular, Cell and Cancer Biology, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/610

► The development of methods and techniques is the driving force of scientific research. In this work, we described two large-scale screens in studying transcriptional… (more)

▼ The development of methods and techniques is the driving force of scientific research. In this work, we described two large-scale screens in studying transcriptional activation and tumor suppression. In Part I, we studied transcriptional activation mechanisms by deriving and characterizing activation defective mutants. Promoter-specific transcriptional activators stimulate transcription through direct interactions with one or more components of the transcription machinery, termed the “target.” The identification of direct in vivo targets of activators has been a major challenge. We perform a large-scale genetic screen to derive and characterize tra1 alleles that are selectively defective for interaction with Gal4 in vivo. Utilizing these mutants, we demonstrated that Tra is an essential target for Gal4 activation, Gal4 and Tra1 bind cooperatively at the promoter and the Gal4–Tra1 interaction occurs predominantly on the promoter. In addition, we demonstrated that the Gal4-interaction site on Tra1 is highly selective. In Part II, we described a functional genomics approach to discover new tumor suppressor genes. A goal of contemporary cancer research is to identify the genes responsible for neoplastic transformation. Cells that are immortalized but non-tumorigenic were stably transduced with pools of short hairpin RNAs (shRNAs) and tested for their ability to form tumors in mice. ShRNAs in any resulting tumors were identified by sequencing to reveal candidate TSGs, which were then validated both experimentally and clinically by analysis of human tumor samples. Using this approach, we identified and validated 33 candidate TSGs. We found that most candidate TSGs were down-regulated in >70% of human lung squamous cell carcinoma (hLSCC) samples, and 17 candidate TSGs negatively regulate FGFR signalling pathway, and their ectopic expression inhibited growth of hLSCC xenografts. Furthermore, we suggest that by examining at the expression level of TSGs in lung cancer patients, we can predict their drug responsiveness to FGFR inhibitors. In conclusion, we have identified many new lung squamous cell cancer TSGs, using an experimental strategy that can be broadly applied to find TSGs in other tumor types. Advisors/Committee Members: Michael R. Green.

Subjects/Keywords: Transcriptional Activation; Genes; Tumor Suppressor; Cells; Genetic Phenomena; Genetics and Genomics; Neoplasms; Nucleic Acids, Nucleotides, and Nucleosides; Respiratory Tract Diseases

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lin, L. (2012). Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/610

Chicago Manual of Style (16^th Edition):

Lin, Ling. “Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/610.

MLA Handbook (7^th Edition):

Lin, Ling. “Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Lin L. Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/610.

Council of Science Editors:

Lin L. Genetic Approaches to Study Transcriptional Activation and Tumor Suppression: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/610

University of Kentucky

8. Pi, Fengmei. RNA Nanotechnology for Next Generation Targeted Drug Delivery.

Degree: 2016, University of Kentucky

URL: https://uknowledge.uky.edu/pharmacy_etds/65

► The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed… (more)

▼ The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies. One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting was developed. The system utilized a highly stable three way junction (3WJ) derived from phi29 bacteriophage packing RNA (pRNA). Instead of using one random loop for aptamer SELEX as traditionally, the divalent RNA nanoparticle library contains two variable loops for substrate binding, similar to protein antibodies. The presence of two binding sites on one aptamer greatly enhanced its affinity, and the thermodynamically stability of pRNA-3WJ motif enables controllable RNA folding of each loop. The selected RNA antibody against epithelial adhesion molecule (EpCAM) A9-8 can deliver therapeutic anti-miR21 to EpCAM positive cancer cells in vitro. The feasibility of using RNA aptamer for targeted chemical drug delivery is explored. A phosphorothioate bond modified DNA (thio-DNA) aptamer targeting annexin A2 was utilized as ligand to build nucleic acid nanoparticles for ovarian cancer targeted drug delivery. A DNA/RNA hybrid nanoparticle was generated by conjugating the thio-DNA aptamer to pRNA-3WJ motif. The DNA/RNA hybrid nanoparticles showed favorable property for delivering doxorubicin to ovarian cancer cells in vitro, also targeted to ovarian cancer xenograft in bio-distribution study in vivo. Utilizing the spatial orientation of pRNA-3WJ, cholesterol modification on the arrow tail of pRNA-3WJ can display RNA nanoparticle on the surface of exosomes/extracellular vesicles (EV) for active targeting. Taking the advantage of RNA ligand for specific targeting; and exosome for efficient membrane fusion, cytosol homing and functional siRNA delivery; the RNA ligand decorated exosomes were constructed for specific delivery of siRNA to cancer cells. PSMA aptamer-displaying exosomes and encapsulated survivin siRNA (PSMAapt/EV/siSurvivin) showed efficient gene silencing both in cell culture and animal trials. After systemically injection of PSMAapt/EV/siSurvivin to prostate cancer xenograft mice, cancer growth was almost completely blocked. These results suggest the advance of RNA nanotechnology can further drive its way towards clinical application as a novel next generation drug delivery system.

Subjects/Keywords: RNA Nanotechnology; Exosome; siRNA; prostate cancer; SELEX; aptamer; Biotechnology; Nanomedicine; Nucleic Acids, Nucleotides, and Nucleosides; Pharmaceutics and Drug Design

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pi, F. (2016). RNA Nanotechnology for Next Generation Targeted Drug Delivery. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/pharmacy_etds/65

Chicago Manual of Style (16^th Edition):

Pi, Fengmei. “RNA Nanotechnology for Next Generation Targeted Drug Delivery.” 2016. Doctoral Dissertation, University of Kentucky. Accessed March 08, 2021. https://uknowledge.uky.edu/pharmacy_etds/65.

MLA Handbook (7^th Edition):

Pi, Fengmei. “RNA Nanotechnology for Next Generation Targeted Drug Delivery.” 2016. Web. 08 Mar 2021.

Vancouver:

Pi F. RNA Nanotechnology for Next Generation Targeted Drug Delivery. [Internet] [Doctoral dissertation]. University of Kentucky; 2016. [cited 2021 Mar 08]. Available from: https://uknowledge.uky.edu/pharmacy_etds/65.

Council of Science Editors:

Pi F. RNA Nanotechnology for Next Generation Targeted Drug Delivery. [Doctoral Dissertation]. University of Kentucky; 2016. Available from: https://uknowledge.uky.edu/pharmacy_etds/65

Michigan Technological University

9. Hou, Shanshan. DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS.

Degree: PhD, Department of Chemistry, 2018, Michigan Technological University

URL: https://digitalcommons.mtu.edu/etdr/729

► Generation of reactive oxygen species (ROS) constantly occurs in healthy cells and is inevitable for aerobic organisms. Controlled ROS production provides the optimal redox… (more)

▼ Generation of reactive oxygen species (ROS) constantly occurs in healthy cells and is inevitable for aerobic organisms. Controlled ROS production provides the optimal redox state for the maintaining proper cellular function. When large amounts of ROS accumulated, oxidative cellular stress occurs. Under conditions of oxidative stress, overproduction of ROS production can lead to damage to membrane lipids, proteins, and nucleic acids. Oxidative damage of these biomolecules is associated with a range of pathophysiological processes, including aging, carcinogenesis, ischemic reperfusion injury, and neuro-degenerative diseases. The pathogeneses of oxidative stress-mediated diseases are complex in nature. Through the use of our newly synthesized fluorescent probes, the role of oxidative damage in the pathogenesis of ischemia/reperfusion injury has been updated. However, there is a need of adequately powered trials to confirm the validity of these fluorescent probes for monitoring cellular response to oxidative damage, initiation of treatment, and reliably assessing therapy efficacy. Towards this, a correlation between oxidative stress and mitochondrial dysfunction was further examined in in vitro and in vivo models of ischemia/reperfusion injury (Chapter 1). Moreover, these newly validated organelle-targetable fluorescent probes and their relevance in the detection of diseases and assessing of treatment efficacy were further investigated in the experimental models of ischemia/ reperfusion injury (Chapter 1) and cancer (Chapter 2). The overproduction of ROS can cause severe damage to cellular macromolecules, especially the DNA. It is important to develop new molecular probes for sensing DNA oxidative damage. Finally, a series of novel nucleic acid-based fluorescent probes are developed (Chapter 3) for biosensing of DNA oxidative damage to alterations in the cellular redox state during hypoxia or oxidative stress. Identification of oxidative DNA damage allows us to have better understanding of how it is implicated in a number of diseases. For my future research direction, I am interested in developing new strategy to improve a cell’s ability to withstand oxidative damage thereby protecting its DNA. I am also interested in finding new ways to increase the activity of DNA repair genes, which may enable the genes to better handle oxidative damage. Advisors/Committee Members: Lanrong Bi.

Subjects/Keywords: ROS; oxidative stress; fluorescent probes; mitochondria; Medicinal and Pharmaceutical Chemistry; Nucleic Acids, Nucleotides, and Nucleosides; Organic Chemicals; Pharmaceutics and Drug Design

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APA (6^th Edition):

Hou, S. (2018). DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS. (Doctoral Dissertation). Michigan Technological University. Retrieved from https://digitalcommons.mtu.edu/etdr/729

Chicago Manual of Style (16^th Edition):

Hou, Shanshan. “DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS.” 2018. Doctoral Dissertation, Michigan Technological University. Accessed March 08, 2021. https://digitalcommons.mtu.edu/etdr/729.

MLA Handbook (7^th Edition):

Hou, Shanshan. “DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS.” 2018. Web. 08 Mar 2021.

Vancouver:

Hou S. DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS. [Internet] [Doctoral dissertation]. Michigan Technological University; 2018. [cited 2021 Mar 08]. Available from: https://digitalcommons.mtu.edu/etdr/729.

Council of Science Editors:

Hou S. DEVELOPING NOVEL MOLECULAR IMAGING AGENTS FOR SHEDDING LIGHT ON OXIDATIVE STRESS. [Doctoral Dissertation]. Michigan Technological University; 2018. Available from: https://digitalcommons.mtu.edu/etdr/729

10. Sinha, Chandrima. MRP4-Dependent Regulation of Fibroblast Migration.

Degree: PhD, Biomedical Sciences, 2014, University of Tennessee Health Science Center

URL: https://dc.uthsc.edu/dissertations/248

► Roles of cyclic nucleotides and cyclic nucleotide-dependent signaling molecules in regulating several signaling pathways including cell migration have long been known. However, the new… (more)

▼ Roles of cyclic nucleotides and cyclic nucleotide-dependent signaling molecules in regulating several signaling pathways including cell migration have long been known. However, the new and revolutionary concept is that it is not just the absence or presence of cyclic nucleotides, but a highly coordinated balance between these molecules regulates cell migration. Multi-drug resistance protein 4 (MRP4), is a member of the large family of ATP binding cassette (ABC) transporter proteins, that localizes to the plasma membrane and functions as a nucleotide efflux transporter and thus plays a pivotal role in the regulation of intracellular cyclic nucleotide dynamics. In our study we used MRP4-expressing fibroblast cells and MRP4 knockout mice as model systems and wound healing assays as the experimental system to explore this unique and emerging concept. Here we demonstrated for the first time that mouse embryonic fibroblasts (MEFs) isolated from Mrp4-/- mice have higher intracellular cyclic nucleotide levels and migrate faster compared to MEFs isolated from Mrp4+/+ mice. Using FRET based sensors specific for cAMP and cGMP we showed that inhibition of MRP4 with MK571 moderately increases both cAMP and cGMP levels and enhances the cell polarization leading to an increased cell migration. Whereas a robust increase in cAMP levels was observed following treatment with forskolin and IBMX, which causes decreased fibroblast migration. Cell migration appeared to be biphasic in response to externally added cell-permeant cyclic nucleotides (cpt-cAMP and cptcGMP). Furthermore we identified actin as an integral part of MRP4-interactome and these two proteins associate with each other predominantly at the plasma membrane. We also observed that actin cytoskeleton restricts MRP4 to the specific micro-domains of plasma membrane. Using FRET based sensor we showed that Mrp4-/- fibroblasts are more polarized compared to the Mrp4+/+ cells with a higher compartmentalized cAMP levels and PKA activities near the leading edge, which in turn lead to an enhanced cortical actin polymerization at the cell front. Taken together our studies suggested a novel cAMP-dependent mechanism for MRP4-mediated regulation of fibroblast migration where PKA and actin play critical roles as downstream targets. Advisors/Committee Members: Kaushik Parthasarathi, Ph.D..

Subjects/Keywords: Actin; Cyclic nucleotides; Fibroblasts; Migration; MRP4; PKA; Chemicals and Drugs; Medical Biochemistry; Medical Cell Biology; Medical Sciences; Medicine and Health Sciences; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Sinha, C. (2014). MRP4-Dependent Regulation of Fibroblast Migration. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/248

Chicago Manual of Style (16^th Edition):

Sinha, Chandrima. “MRP4-Dependent Regulation of Fibroblast Migration.” 2014. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed March 08, 2021. https://dc.uthsc.edu/dissertations/248.

MLA Handbook (7^th Edition):

Sinha, Chandrima. “MRP4-Dependent Regulation of Fibroblast Migration.” 2014. Web. 08 Mar 2021.

Vancouver:

Sinha C. MRP4-Dependent Regulation of Fibroblast Migration. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2014. [cited 2021 Mar 08]. Available from: https://dc.uthsc.edu/dissertations/248.

Council of Science Editors:

Sinha C. MRP4-Dependent Regulation of Fibroblast Migration. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2014. Available from: https://dc.uthsc.edu/dissertations/248

11. Martinez, Natalia Julia. Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation.

Degree: Interdisciplinary Graduate Program, Program in Molecular Medicine, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/411

► Metazoan genomes contain thousands of protein-coding and non-coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during… (more)

▼ Metazoan genomes contain thousands of protein-coding and non-coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans-regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis-regulatory DNA elements that are often located in or near their target genes, while microRNAs hybridize to cis-regulatory RNA elements mostly located in the 3’ untranslated region (3’UTR) of their target mRNAs. My work in the Walhout lab has centered on understanding how these trans-regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome-scale level. Our model organism is the free-living nematode Caenorahbditis elegans, which possess approximately 950 predicted TFs and more than 100 miRNAs Whereas much attention has focused on finding the protein-coding target genes of both miRNAs and TFs, the transcriptional networks that regulate miRNA expression remain largely unexplored. To this end, we have embarked in the task of mapping the first genome-scale miRNA regulatory network. This network contains experimentally mapped transcriptional TF=>miRNA interactions, as well as computationally predicted post-transcriptional miRNA=>TF interactions. The work presented here, along with data reported by other groups, have revealed the existence of reciprocal regulation between these two types of regulators, as well as extensive coordination in the regulation of shared target genes. Our studies have also identified common mechanisms by which miRNAs and TFs function to control gene expression and have suggested an inherent difference in the network properties of both types of regulators. Reverse genetic approaches have been extensively used to delineate the biological function of protein-coding genes. For instance, genome-wide RNAi screens have revealed critical roles for TFs in C. elegans development and physiology. However, reverse genetic approaches have not been very insightful in the case of non-coding genes: A single null mutation does not result in an easily detectable phenotype for most C. elegans miRNA genes. To help delineate the biological function of miRNAs we sought to determine when and where they are expressed. Specifically, we generated a collection of transgenic C. elegans strains, each containing a miRNA promoter::gfp (Pmir::gfp) fusion construct. The particular pattern of expression of each miRNA gene should help to identify potential genetic interactors that exhibit similar expression patterns, and to design experiments to test the phenotypes of miRNA mutants. Advisors/Committee Members: Marian Walhout Ph.D..

Subjects/Keywords: Transcription Factors; MicroRNAs; Gene Expression Regulation; Caenorhabditis elegans; Genes; Helminth; Transcription; Genetic; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Martinez, N. J. (2009). Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/411

Chicago Manual of Style (16^th Edition):

Martinez, Natalia Julia. “Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/411.

MLA Handbook (7^th Edition):

Martinez, Natalia Julia. “Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation.” 2009. Web. 08 Mar 2021.

Vancouver:

Martinez NJ. Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/411.

Council of Science Editors:

Martinez NJ. Delineating the C. elegans MicroRNA Regulatory Network: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/411

12. Ghildiyal, Megha. Endogenous Small RNAs in the Drosophila Soma: A Dissertation.

Degree: Interdisciplinary Graduate Program, RNA Therapeutics Institute, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/459

► Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNAs have been identified, including microRNAs (miRNAs), small… (more)

▼ Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNAs have been identified, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). These classes differ in their biogenesis, modes of target regulation and in the biological pathways they regulate. Historically, siRNAs were believed to arise only from exogenous double-stranded RNA triggers in organisms lacking RNA-dependent RNA polymerases. However, the discovery of endogenous siRNAs in flies expanded the biological significance of siRNAs beyond viral defense. By high throughput sequencing we identified Drosophila endosiRNAs as 21 nt small RNAs, bearing a 2´-O-methyl group at their 3´ ends, and depleted in dicer-2 mutants. Methylation of small RNAs at the 3´ end in the soma, is a consequence of assembly into a mature Argonaute2-RNA induced silencing complex. In addition to endo-siRNAs, we observed certain miRNAs or their miRNA* partners loading into Argonaute2. We discovered, that irrespective of its biogenesis, a miRNA duplex can load into either Argonaute (Ago1 or Ago2), contingent on its structural and sequence features, followed by assignment of one of the strands in the duplex as the functional or guide strand. Usually the miRNA strand is selected as the guide in complex with Ago1 and miRNA* strand with Ago2. In our efforts towards finding 3´ modified small RNAs in the fly soma, we also discovered 24-28nt small RNAs in certain fly genotypes, particularly ago2 and dcr-2mutants. 24-28nt small RNAs share many features with piRNAs present in the germline, and a significant fraction of the 24-28nt small RNAs originate from similar transposon clusters as somatic endo-siRNAs. Therefore the same RNA can potentially act as a precursor for both endo-siRNA and piRNA-like small RNA biogenesis. We are analyzing the genomic regions that spawn somatic small RNAs in order to understand the triggers for their production. Ultimately, we want to attain insight into the underlying complexity that interconnects these small RNA pathways. Dysregulation of small RNAs leads to defects in germline development, organogenesis, cell growth and differentiation. This thesis research provides vital insight into the network of interactions that fine-tune the small RNA pathways. Understanding the flow of information between the small RNA pathways, a great deal of which has been revealed only in the recent years, will help us comprehend how the pathways compete and collaborate with each other, enabling each other’s optimum function. Advisors/Committee Members: Phillip D. Zamore, Ph.D..

Subjects/Keywords: Drosophila; Drosophila Proteins; RNA; Untranslated; RNA; Small Interfering; MicroRNAs; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Cells; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ghildiyal, M. (2010). Endogenous Small RNAs in the Drosophila Soma: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/459

Chicago Manual of Style (16^th Edition):

Ghildiyal, Megha. “Endogenous Small RNAs in the Drosophila Soma: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/459.

MLA Handbook (7^th Edition):

Ghildiyal, Megha. “Endogenous Small RNAs in the Drosophila Soma: A Dissertation.” 2010. Web. 08 Mar 2021.

Vancouver:

Ghildiyal M. Endogenous Small RNAs in the Drosophila Soma: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/459.

Council of Science Editors:

Ghildiyal M. Endogenous Small RNAs in the Drosophila Soma: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/459

13. Pagano, John M., Jr. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology Program, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/486

► Post-transcriptional regulation of gene expression is a mechanism that governs developmental and cellular events in metazoans. In early embryogenesis, transcriptionally quiescent cells depend upon… (more)

▼ Post-transcriptional regulation of gene expression is a mechanism that governs developmental and cellular events in metazoans. In early embryogenesis, transcriptionally quiescent cells depend upon maternally supplied factors such as RNA binding proteins and RNA that control key decisions. Morphogen gradients form and in turn pattern the early embryo generating different cell types and spatial order. In the nematode Caenorhabditis elegans, the early embryo relies upon several RNA binding proteins that control mRNA stability, translation efficiency, and/or mRNA localization of cell fate determinants essential for proper development. MEX-5 and MEX-3 are two conserved RNA-binding proteins required to pattern the anterior/posterior axis and early embryo. Mutation of either gene results in a maternal effect lethal phenotype with proliferating posterior muscle into the anterior blastomeres (Muscle EXcess). Several cell-fate determinants are aberrantly expressed in mex-5 and mex-3 embryos. Both proteins are thought to interact with cis-regulatory elements present in 3’-UTRs of target RNAs controlling their metabolism. However, previous studies failed to demonstrate that these proteins regulate maternal transcripts directly. This dissertation presents a thorough assessment of the RNA binding properties of MEX-5 and MEX-3. Quantitative biochemical approaches were used to determine the RNA binding specificity of both proteins. MEX-5 has a relaxed specificity, binding with high affinity to linear RNA containing a tract of six or more uridines within an eight-nucleotide window. This is very different from its mammalian homologs Tristetraprolin (TTP) and ERF-2. I was able to identify two amino acids present within the MEX-5 RNA binding domain that are required for the differential RNA recognition observed between MEX-5 and TTP. MEX-3 on the other hand is a specific RNA binding protein, recognizing a bipartite element with flexible spacing between two four-nucleotide half-sites. I demonstrate that this element is required for MEX-3 dependent regulation in vivo. Previous studies only identify a small number of candidate regulatory targets of MEX-5 and MEX-3. The defined sequence specificity of both proteins is used to predict new putative targets that may be regulated by either protein. Collectively, this study examines the RNA binding properties of MEX-5 and MEX-3 to clarify their role as post-transcriptional regulators in nematode development. Advisors/Committee Members: Sean Ryder, PhD.

Subjects/Keywords: Caenorhabditis elegans Proteins; RNA-Binding Proteins; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Biochemistry, Biophysics, and Structural Biology; Cells; Embryonic Structures; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pagano, John M., J. (2010). RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/486

Chicago Manual of Style (16^th Edition):

Pagano, John M., Jr. “RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/486.

MLA Handbook (7^th Edition):

Pagano, John M., Jr. “RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.” 2010. Web. 08 Mar 2021.

Vancouver:

Pagano, John M. J. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/486.

Council of Science Editors:

Pagano, John M. J. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/486

14. O'Brien, Siobhan. Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Program in Biochemistry and Molecular Pharmacology, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/528

► RNA polymerase II-mediated transcription of HIV-1 genes depends on positive transcription elongation factor b (P-TEFb), the complex of cyclin T1 and CDK9. Recent evidence… (more)

Subjects/Keywords: Positive Transcriptional Elongation Factor B; RNA Polymerase II; Transcription Factors; HIV-1; Amino Acids, Peptides, and Proteins; Genetics and Genomics; Nucleic Acids, Nucleotides, and Nucleosides; Viruses

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

O'Brien, S. (2010). Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/528

Chicago Manual of Style (16^th Edition):

O'Brien, Siobhan. “Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/528.

MLA Handbook (7^th Edition):

O'Brien, Siobhan. “Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation.” 2010. Web. 08 Mar 2021.

Vancouver:

O'Brien S. Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/528.

Council of Science Editors:

O'Brien S. Regulation of Cellular and HIV-1 Gene Expression by Positive Transcription Elongation Factor B: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/528

15. Li, Chengjian. Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, RNA Therapeutics Institute, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/524

► In the Drosophila germ line, PIWI-interacting RNAs (piRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences. We… (more)

▼ In the Drosophila germ line, PIWI-interacting RNAs (piRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences. We examined the genetic requirements for the biogenesis and function of piRNAs in both female and male germ line. We found that piRNAs function through the PIWI, rather than the AGO, family Argonaute proteins, and the production of piRNAs requires neither microRNA (miRNA) nor small interfering RNA (siRNA) pathway machinery. These findings allowed the discovery of the third conserved small RNA silencing pathway, which is distinct from both the miRNA and RNAi pathways in its mechanisms of biogenesis and function. We also found piRNAs in flies are modified. We determined that the chemical structure of the 3´-terminal modification is a 2´-O-methyl group, and also demonstrated that the same modification occurs on the 3´ termini of siRNAs in flies. Furthermore, we identified the RNA methyltransferase Drosophila Hen1, which catalyzes 2´-O-methylation on both siRNAs and piRNAs. Our data suggest that 2´-O-methylation by Hen1 is the final step of biogenesis of both the siRNA pathway and piRNA pathway. Studies from the Hannon Lab and the Siomi Lab suggest a ping-pong amplification loop for piRNA biogenesis and function in the Drosophila germline. In this model, an antisense piRNA, bound to Aubergine or Piwi, triggers production of a sense piRNA bound to the PIWI protein Argonaute3 (Ago3). In turn, the new piRNA is envisioned to produce a second antisense piRNA. We isolated the loss-of-function mutations in ago3, allowing a direct genetic test of this model. We found that Ago3 acts to amplify piRNA pools and to enforce on them an antisense bias, increasing the number of piRNAs that can act to silence transposons. Moreover, we also discovered a second Ago3-independent piRNA pathway in somatic ovarian follicle cells, suggesting a role for piRNAs beyond the germ line. Advisors/Committee Members: Phillip D. Zamore, Ph.D..

Subjects/Keywords: Drosophila; Drosophila Proteins; RNA; Small Interfering; Germ Cells; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Biochemistry, Biophysics, and Structural Biology; Cells; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, C. (2011). Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/524

Chicago Manual of Style (16^th Edition):

Li, Chengjian. “Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/524.

MLA Handbook (7^th Edition):

Li, Chengjian. “Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation.” 2011. Web. 08 Mar 2021.

Vancouver:

Li C. Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/524.

Council of Science Editors:

Li C. Molecular Mechanisms of piRNA Biogenesis and Function in Drosophila: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/524

16. Cottonham, Charisa L. The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation.

Degree: Interdisciplinary Graduate Program, Program in Molecular Medicine, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/530

► The function of transforming growth factor β (TGF-β) in cancer is notoriously complex. Initially TGF-β limits tumorigenesis, but at later stages in tumor progression… (more)

▼ The function of transforming growth factor β (TGF-β) in cancer is notoriously complex. Initially TGF-β limits tumorigenesis, but at later stages in tumor progression TGF-β promotes the malignant spread of tumor cells. Past studies to understand the pro-metastasis utility of TGF-β centered upon its ability to regulate protein-coding genes. Recently, a small class of non-coding RNAs known as microRNAs (miRNAs) emerged as novel posttranscriptional regulators of gene expression. The significance of miRNA function in cellular processes from embryonic development to the maintenance of homeostasis in adult tissues is becoming increasingly clear. Also apparent is the strong association between aberrant miRNA expression and human diseases, such as cancer. The contribution of miRNAs to TGF-β-mediated cellular responses remains an open question. Thus, I became interested if miRNAs offered an additional layer of regulation in TGF-β signaling through which this cytokine exerts its pro-metastasis function. To address this inquiry, in the first part of this dissertation I investigated whether miRNAs influenced the ability of TGF-β to induce cellular responses directly involved with carcinoma metastasis, such as epithelial-mesenchymal transition (EMT). Here, I identified two miRNAs, miR-21 and miR-31, that are upregulated during EMT in LIM 1863 organoids, a colon carcinoma model of EMT driven by TGF-β. We performed in vitro studies to characterize the function of miR-21 and miR-31 and found that these two miRNAs positively impact the induction of EMT, migration and invasion by TGF-β. Furthermore, we uncovered TIAM1 (T lymphoma and metastasis gene 1) as a novel target of both miR-21 and miR-31 and show that downregulation of TIAM1 is critical for the pro-migration and pro-invasion activities of miR-21 and miR-31. Together these findings reveal miR-21 and miR-31 as downstream effectors of TGF-β signaling by facilitating EMT, migration and invasion of colon carcinoma cells. How TGF-β regulates miR-21 and miR-31 became important questions and thus the focus of the second part of this thesis. Interestingly, I found that TGF-β and TNF-α synergize to increase miR-21 and miR-31 levels in LIM 1863 organoids and that the synthesis of new factors induced by TGF-β/TNF-α are required for this upregulation. Moreover, I report that regulation of miR-21 by TGF-β/TNF-α occurs at multiple levels of biogenesis. More specifically data provided here show that Smad4 binds to the promoter of miR-21 to upregulate its expression thereby specifying miR-21 as a typical TGF-β target gene. This mechanism is different from one recently observed in smooth muscle cells in which TGF-β did not stimulate miR-21 transcription, but interestingly, Smad4 enhanced the Drosha-mediated processing of the miR-21 precursor. These two mechanisms suggest that TGF-β regulation of miR-21 is contextual and highlight the complexity of TGF-β signaling. As a whole, my findings establish important roles for miR-21 and miR-31… Advisors/Committee Members: Lan Xu, Ph.D..

Subjects/Keywords: MicroRNAs; Transforming Growth Factor beta; Gene Expression Regulation; Amino Acids, Peptides, and Proteins; Biological Factors; Cancer Biology; Cells; Genetic Phenomena; Neoplasms; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cottonham, C. L. (2011). The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/530

Chicago Manual of Style (16^th Edition):

Cottonham, Charisa L. “The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/530.

MLA Handbook (7^th Edition):

Cottonham, Charisa L. “The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation.” 2011. Web. 08 Mar 2021.

Vancouver:

Cottonham CL. The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/530.

Council of Science Editors:

Cottonham CL. The Role of miR-21 and miR-31 in Cellular Responses Mediated by TGF-β: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/530

17. Doherty, Johnna E. Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation.

Degree: Neuroscience, Department of Neurobiology; Freeman Lab, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/577

► The nervous system is made up of two major cell types, neurons and glia. The major distinguishing feature between neuronal cells and glial cells… (more)

▼ The nervous system is made up of two major cell types, neurons and glia. The major distinguishing feature between neuronal cells and glial cells is that neurons are capable of transmitting action potentials while glial cells are electrically incompetent. For over a century glial cells were neglected and it was thought they existed merely to provide trophic and structural support to neurons. However, in the past few decades it has become increasingly clear that glial cell functions underlie almost all aspects of nervous system development, maintenance, and health. During development, glia act as permissive substrates for axons, provide guidance cues, regulate axon bundling, facilitate synapse formation, refine synaptic connections, and promote neuronal survival. In the mature nervous system glial cells regulate adult neurogenesis through phagocytosis, act as the primary immune cell, and contribute to complex processes such as learning and memory. In recent years, glial cells have also become a primary focus in the study of neurodegenerative diseases. Mounting evidence shows that glial cells exert both beneficial as well as detrimental effects in the pathology of several nervous system disorders, and modulation of glial activity is emerging as a viable therapeutic strategy for many diseases. Although glial cells are critical to the proper development and functioning of the nervous system, there is still relatively little known about the molecular mechanisms used by glial cells, how they exert their effects on neurons, and how glia and neurons communicate. Despite the relative simplicity and small size of the Drosophila nervous system, glial cell organization and function in flies shows a remarkable complexity similar to vertebrate glial cells. In this study I use Drosophila as a model organism to study cellular and molecular mechanisms of glial clearance of axonal debris after acute axotomy. In chapter two of this thesis, I characterize three distinct subtypes of glial cells in the adult brain; cell body glia which ensheath neuronal cell bodies in the cortex region of the brain, astrocyte like glial cells which bear striking morphological similarity to mammalian astrocytes and share common molecular components, and ensheathing glial cells which I show act as the primary phagocytic cell type in the neuropil region of the brain. In addition, I identify dCed-6, the ortholog of mammalian GULP, as a necessary component of the glial phagocytic machinery. In chapter three of this thesis, I perform a candidate based, in vivo, RNAi screen to identify novel genes involved in the glial engulfment of degenerating axon material. The Gal4/UAS system was used to drive UAS-RNAi for approximately 300 candidate genes with the glial specific repo-Gal4 driver. Two assays were used as a readout in this screen, clearance of axon material five days after injury, and Draper upregulation one day after maxillary palp or antennal injury. Overall, I identified 20 genes which, when knocked down… Advisors/Committee Members: Marc Freeman, Ph.D..

Subjects/Keywords: Neuroglia; Neurons; Drosophila Proteins; Axons; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Cells; Nervous System; Neuroscience and Neurobiology; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Doherty, J. E. (2011). Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/577

Chicago Manual of Style (16^th Edition):

Doherty, Johnna E. “Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/577.

MLA Handbook (7^th Edition):

Doherty, Johnna E. “Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation.” 2011. Web. 08 Mar 2021.

Vancouver:

Doherty JE. Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/577.

Council of Science Editors:

Doherty JE. Cellular and Molecular Mechanisms Driving Glial Engulfment of Degenerating Axons: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/577

18. Lin, Chien-Ling. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.

Degree: Interdisciplinary Graduate Program, Program in Molecular Medicine, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/583

► Post-transcriptional regulation of gene expression sits at the core of proteomic complexity; trans-acting factors that regulate RNA localization and translation capacity are thus indispensible.… (more)

Subjects/Keywords: RNA-Binding Proteins; Poly(A)-Binding Proteins; Polyadenylation; Amino Acids, Peptides, and Proteins; Biochemical Phenomena, Metabolism, and Nutrition; Biochemistry, Biophysics, and Structural Biology; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Lin, C. (2012). Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/583

Chicago Manual of Style (16^th Edition):

Lin, Chien-Ling. “Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/583.

MLA Handbook (7^th Edition):

Lin, Chien-Ling. “Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Lin C. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/583.

Council of Science Editors:

Lin C. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/583

19. Merrikh, Christopher N. Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, RNA Therapeutics Institute, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/613

► The molecular biology revolution of the 1960s has given rise to an enormous body of literature describing, in great detail, the inner workings of… (more)

Subjects/Keywords: RNA Stability; RNA; Ribosomal; 18S; Saccharomyces cerevisiae Proteins; Amino Acids, Peptides, and Proteins; Biochemistry, Biophysics, and Structural Biology; Cells; Fungi; Molecular Biology; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Merrikh, C. N. (2012). Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/613

Chicago Manual of Style (16^th Edition):

Merrikh, Christopher N. “Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/613.

MLA Handbook (7^th Edition):

Merrikh, Christopher N. “Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Merrikh CN. Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/613.

Council of Science Editors:

Merrikh CN. Characterization of New Factors in the 18S Nonfunctional Ribosomal RNA Decay Pathway in S. cerevisiae: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/613

20. Laine, Jennifer M. Protein Ligand Interactions Probed by NMR: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology Program, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/617

► Molecular recognition, defined as the specific interactions between two or more molecules, is at the center of many biological processes including catalysis, signal transduction,… (more)

▼ Molecular recognition, defined as the specific interactions between two or more molecules, is at the center of many biological processes including catalysis, signal transduction, gene regulation and allostery. Allosteric regulation is the modification of function caused by an intermolecular interaction. Allosteric proteins modify their activity in response to a biological signal that is often transmitted through the interaction with a small effector molecule. Therefore, determination of the origins of intermolecular interactions involved in molecular recognition and allostery are essential for understanding biological processes. Classically, molecular recognition and allosteric regulation have been associated to structural changes of the system. NMR spectroscopic methods have indicated that changes in protein dynamics may also contribute to molecular recognition and allostery. This thesis is an investigation of the contributions of both structure and dynamics in molecular binding phenomena. In chapter I, I describe molecular recognition, allostery and examples of allostery and cooperativity. Then I discuss the contribution of protein dynamics to function with a special focus on allosteric regulation. Lastly I introduce the hemoglobin homodimer, HbI of Scapharca inaequivalvis and the mRNA binding protein TIS11d. Chapter II is the primary focus of this thesis on the contribution of protein dynamics to allostery in the dimeric hemoglobin of scapharca inaequivalvis, HbI. Thereafter I concentrate on the mechanism of adenine recognition of the Tristetraprolin-like (TTP) protein TIS11d; this study is detailed in Chapter III. In Chapter IV I discuss broader impacts and future directions of my research. This thesis presents an example of the use of protein NMR spectroscopy to probe ligand binding. The studies presented in this thesis emphasize the importance of dynamics in understanding protein function. Measurements of protein motions will be an element of future studies to understand protein function in health and disease. Advisors/Committee Members: Francesca Massi, Ph.D..

Subjects/Keywords: Ligands; Nuclear Magnetic Resonance; Biomolecular; Molecular Conformation; Protein Binding; Allosteric Regulation; Amino Acids, Peptides, and Proteins; Chemical Actions and Uses; Investigative Techniques; Molecular Biology; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Laine, J. M. (2012). Protein Ligand Interactions Probed by NMR: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/617

Chicago Manual of Style (16^th Edition):

Laine, Jennifer M. “Protein Ligand Interactions Probed by NMR: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/617.

MLA Handbook (7^th Edition):

Laine, Jennifer M. “Protein Ligand Interactions Probed by NMR: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Laine JM. Protein Ligand Interactions Probed by NMR: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/617.

Council of Science Editors:

Laine JM. Protein Ligand Interactions Probed by NMR: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/617

21. Perrat, Paola N. Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation.

Degree: Neuroscience, Department of Neurobiology; Waddell Lab, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/622

► In the Drosophila brain, memories are processed and stored in two mirrorsymmetrical structures composed of approximately 5,000 neurons called Mushroom Bodies (MB). Depending on… (more)

▼ In the Drosophila brain, memories are processed and stored in two mirrorsymmetrical structures composed of approximately 5,000 neurons called Mushroom Bodies (MB). Depending on their axonal extensions, neurons in the MB can be further classified into three different subgroups: αβ, α’β’ and γ. In addition to the morphological differences between these groups of neurons, there is evidence of functional differences too. For example, it has been previously shown that while neurotransmission from α’β’ neurons is required for consolidation of olfactory memory, output from αβ neurons is required for its later retrieval. To gain insight into the functional properties of these discrete neurons we analyzed whether they were different at the level of gene expression. We generated an intersectional genetic approach to exclusively label each population of neurons and permit their purification. Comparing expression profiles, revealed a large number of potentially interesting molecular differences between the populations. We focused on the finding that the MB αβ neurons, which are the presumed storage site for transcription-dependent long-term memory, express high levels of mRNA for transposable elements and histones suggesting that these neurons likely possess unique genomic characteristics. For decades, transposable elements (TE) were considered to be merely “selfish” DNA elements inserted at random in the genome and that they their sole function was to self-replicate. However, new studies have started to arise that indicate TE contribute more than just “junk” DNA to the genome. Although it is widely believed that mobilization of TE destabilize the genome by insertional mutagenesis, deletions and rearrangements of genes, some rearrangements might be advantageous for the organism. TE mobilization has recently been documented to occur in some somatic cells, including in neuronal precursor cells (NPCs). Moreover, mobilization in NPCs seems to favor insertions within neuronal expressed genes and in one case the insertion elevated the expression. During the last decade, the discovery of the small RNA pathways that suppress the expression and mobilization of TE throughout the animal have helped to uncover new functions that TE play. In this work, we demonstrate that proteins of the PIWI-associated RNA pathway that control TE expression in the germline are also required to suppress TE expression in the adult fly brain. Moreover, we find that they are differentially expressed in subsets of MB neurons, being under represented in the αβ neurons. This finding suggests that the αβ neurons tolerate TE mobilization. Lastly, we demonstrate by sequencing αβ neuron DNA that TE are mobile and we identify >200 de novo insertions into neurally expressed genes. We conclude that this TE generated mosaicism, likely contributes a new level of neuronal diversity making, in theory, each αβ neuron genetically different. In principle the stochastic nature of this process could also render every fly an individual. Advisors/Committee Members: Scott Waddell Ph.D..

Subjects/Keywords: Drosophila; neurons; Mushroom Bodies; Drosophila Proteins; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Genetic Phenomena; Genetics and Genomics; Nervous System; Neuroscience and Neurobiology; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Perrat, P. N. (2012). Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/622

Chicago Manual of Style (16^th Edition):

Perrat, Paola N. “Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/622.

MLA Handbook (7^th Edition):

Perrat, Paola N. “Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Perrat PN. Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/622.

Council of Science Editors:

Perrat PN. Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/622

22. Gerson, Kristin D. Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation.

Degree: PhD, Molecular, Cell and Cancer Biology, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/588

► The development and survival of multicellular organisms depends upon the ability of cells to move. Embryogenesis, immune surveillance, wound healing, and metastatic disease are… (more)

▼ The development and survival of multicellular organisms depends upon the ability of cells to move. Embryogenesis, immune surveillance, wound healing, and metastatic disease are all processes that necessitate effective cellular locomotion. Central to the process of cell motility is the family of integrins, transmembrane cell surface receptors that mediate stable adhesions between cells and their extracellular environment. Many human diseases are associated with aberrant integrin function. Carcinoma cells in particular can hijack integrins, harnessing their mechanical and signaling potential to propagate cell invasion and metastatic disease, one example being integrin α6β4. This integrin, often referred to simply as β4, is defined as an adhesion receptor for the laminin family of extracellular matrix proteins. The role of integrin β4 in potentiating carcinoma invasion is well established, during which it serves both a mechanical and signaling function. miRNAs are short non-coding RNAs that regulate gene expression posttranscriptionally, and data describing the role of extracellular stimuli in governing their expression patterns are sparse. This observation coupled to the increasingly significant role of miRNAs in tumorigenesis prompted us to examine their function as downstream effectors of β4, an integrin closely linked to aggressive disease in breast carcinoma. The work presented in this dissertation documents the first example that integrin expression correlates with specific miRNA patterns. Moreover, integrin β4 status in vitro and in vivo is associated with decreased expression of distinct miRNA families in breast cancer, namely miR-25/32/92abc/363/363-3p/367 and miR-99ab/100, with purported roles in cell motility. Another miRNA, miR-29a, is significantly downregulated in response to de novo expression of β4 in a breast carcinoma cell line, and β4-mediated repression of the miRNA is required for invasion. Another major conclusion of this study is that β4 integrin expression and ligation can regulate the expression of SPARC in breast carcinoma cells. These data reveal distinct mechanisms by which β4 promotes SPARC expression, involving both a miR-29a-mediated process and a TOR-dependent translational mechanism. Our observations establish a link between miRNA expression patterns and cell motility downstream of β4 in the context of breast cancer, and uncover a novel effector of β4-mediated invasion. Advisors/Committee Members: Arthur M. Mercurio PhD.

Subjects/Keywords: Breast Neoplasms; Integrin alpha6beta4; Cell Movement; MicroRNAs; Neoplasm Invasiveness; Amino Acids, Peptides, and Proteins; Cancer Biology; Neoplasms; Nucleic Acids, Nucleotides, and Nucleosides; Skin and Connective Tissue Diseases

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APA (6^th Edition):

Gerson, K. D. (2012). Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/588

Chicago Manual of Style (16^th Edition):

Gerson, Kristin D. “Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/588.

MLA Handbook (7^th Edition):

Gerson, Kristin D. “Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation.” 2012. Web. 08 Mar 2021.

Vancouver:

Gerson KD. Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/588.

Council of Science Editors:

Gerson KD. Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/588

University of Kentucky

23. Hayden, Reiya. ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS.

Degree: 2020, University of Kentucky

URL: https://uknowledge.uky.edu/pharmacy_etds/120

► Introduction: Chromosomal translocations are common in cancer. In many cancers such as prostate cancer, leukemia and Ewing sarcoma, chromosomal translocations are the main driver of… (more)

▼ Introduction: Chromosomal translocations are common in cancer. In many cancers such as prostate cancer, leukemia and Ewing sarcoma, chromosomal translocations are the main driver of malignancy. Ewing sarcoma is a cancer diagnosed mostly in children and adolescents that has very grim outcomes for patients with metastasis and recurrent disease. Malignancy in Ewing sarcoma is due to EWS-FLI1, an aberrant transcription factor that is the result of a chromosomal translocation. EWS-FLI1 is the main driver of oncogenesis in Ewing sarcoma and has been the target of many drugs developed to treat the disease. Mithramycin (MTM) was identified as a potent inhibitor of EWS-FLI1, but despite its pre-clinical success there were serious toxicities associated with its use including hepatotoxicity. Adverse effects associated with MTM treatment resulted in treatment regimens that were not enough to decrease tumor size. Because of dose limiting toxicities there has been a collective effort to develop analogues of MTM that are less toxic but more effective against inhibiting EWS-FLI1 activity. Here I present an assessment of the unique molecular biologic activity of novel MTM analogues. Preliminary pharmacokinetic studies have shown that in mice MTM has a shorter plasma half-life of about five hours [1]. MTM analogues MTMSA-TRP and MTMSA-TRP-TRP have extended plasma half-lives of twelve hours and over eighteen hours, respectively. Due to their longer plasma half-lives we hypothesized that MTM analogues have less affinity for organic anion transporting polypeptides (OATP) because of their physiochemical properties. Additionally, DNA binding assays suggested that MTM analogues bind DNA and stabilize the EWS-FLI1 transcription factor reducing transcription of EWS-FLI1 target genes [2]. We hypothesize that MTM analogues bind DNA displacing and/or stabilizing EWS-ETS transcription factors. These analogues bind DNA resulting in DNA damage, we hypothesize that combining MTM analogues that cause DNA damage with PARP1 inhibitors will result in a synergistic response in cell lines expressing EWS-FLI1. Methods: Based on preliminary cytotoxicity and pharmacokinetic studies, the ionization constant (pKa) of MTM and analogues was measured. Based on the fluorescence of MTM core aromatic rings at increasing pH, pKa values were estimated. RKO cells stably transfected with pIRES/OATP1B1 or pIRES/OATP1B3 expression vectors were used to complete competitive inhibition studies. Measuring MTM and analogue competition into OATP vs. 8- (2- [fluoresceinyl]aminoethylthio) adenosine- 3', 5'- cyclic monophosphate (8-FcA), a fluorescent substrate of OATP transporters. OATP expressing cells were also subjected to cytotoxicity studies to evaluate uptake of MTM analogues over a 72-hour assay. FVB/N Oatp1a/1b knockout (KO) and FVB/N wildtype mice were used to complete pharmacokinetic studies evaluating differences in uptake of MTM and MTMSA-TRP-TRP after pre-treatment with the OATP inhibitor rifampicin for 1 hour. Time-resolved fluorescent energy transfer (TR-FRET)…

Subjects/Keywords: Mithramycin; Ewing Sarcoma; OATP; DNA damage; olaparib; EWS-FLI1; Amino Acids, Peptides, and Proteins; Medical Molecular Biology; Nucleic Acids, Nucleotides, and Nucleosides; Pharmacology; Pharmacology, Toxicology and Environmental Health

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hayden, R. (2020). ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/pharmacy_etds/120

Chicago Manual of Style (16^th Edition):

Hayden, Reiya. “ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS.” 2020. Doctoral Dissertation, University of Kentucky. Accessed March 08, 2021. https://uknowledge.uky.edu/pharmacy_etds/120.

MLA Handbook (7^th Edition):

Hayden, Reiya. “ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS.” 2020. Web. 08 Mar 2021.

Vancouver:

Hayden R. ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS. [Internet] [Doctoral dissertation]. University of Kentucky; 2020. [cited 2021 Mar 08]. Available from: https://uknowledge.uky.edu/pharmacy_etds/120.

Council of Science Editors:

Hayden R. ELUCIDATING MOLECULAR FUNCTION OF MITHRAMYCIN AND ANALOGUES FOR THE TREATMENT OF EWS-ETS EXPRESSING CANCERS. [Doctoral Dissertation]. University of Kentucky; 2020. Available from: https://uknowledge.uky.edu/pharmacy_etds/120

24. Ward, Jeanine. MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis.

Degree: MSin Clinical Investigation, Emergency Medicine, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/625

► Background To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice. Methods Using plasma from… (more)

Subjects/Keywords: MicroRNAs; Acetaminophen; Animal Experimentation and Research; Digestive System; Nucleic Acids, Nucleotides, and Nucleosides; Organic Chemicals; Pharmaceutical Preparations; Pharmacology, Toxicology and Environmental Health; Therapeutics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ward, J. (2012). MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis. (Masters Thesis). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/625

Chicago Manual of Style (16^th Edition):

Ward, Jeanine. “MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis.” 2012. Masters Thesis, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/625.

MLA Handbook (7^th Edition):

Ward, Jeanine. “MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis.” 2012. Web. 08 Mar 2021.

Vancouver:

Ward J. MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis. [Internet] [Masters thesis]. U of Massachusetts : Med; 2012. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/625.

Council of Science Editors:

Ward J. MicroRNA Markers of Acetaminophen Toxicity: A Master's Thesis. [Masters Thesis]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/625

25. Munroe, David. mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis.

Degree: Molecular Genetics and Microbiology, Microbiology and Physiological Systems, 1999, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/67

► Most eukaryotic mRNAs have a sequence of polyadenylic acid [poly(A)] at their 3'-termini. Although it has been almost two decades since the discovery of… (more)

▼ Most eukaryotic mRNAs have a sequence of polyadenylic acid [poly(A)] at their 3'-termini. Although it has been almost two decades since the discovery of these poly(A) tracts, their function(s) have yet to be clarified. Earlier results from our laboratory led us to propose that poly(A) has a role in translation. More specifically, we proposed that an interaction of the cytoplasmic poly(A)-binding protein (PABP) with a critical minimum length of poly(A) facilitates the initiation of translation of poly(A)⁺, but not poly(A)^-, mRNAs. The results of several different experimental approaches have provided evidence which indirectly supports this hypothesis. These results include: 1) the correlation of specific changes in mRNA poly(A) tail length with translational efficiency in vivo and in vitro; 2) correlations between the abundance and stability of PABPs and the rate of translational initiation in vivo and in vitro; and 3) the demonstration that exogenous poly(A) is a potent and specific inhibitor of the in vitro translation of poly(A)⁺, but not poly(A)^-mRNAs. To evaluate the hypothesis that the 3'-poly(A) tract of mRNA plays a role in translational initiation, we have constructed derivatives of pSP65 which direct the in vitro synthesis of mRNAs with different poly(A) tail lengths and compared, in reticulocyte extracts, the relative efficiencies with which such mRNAs are translated, degraded, recruited into polysomes, and assembled into mRNPs or intermediates in the translational initiation pathway. Relative to mRNAs which are polyadenylated, we find that poly(A)^- mRNAs have a reduced translational capacity which is not due to an increase in their decay rates, but is attributable to a reduction in their efficiency of recruitment into polysomes. The defect in poly(A)^- mRNAs affects a late step in translational initiation, is distinct from the phenotype associated with cap-deficient mRNAs, and results in a reduced ability to form 80S initiation complexes. Moreover, poly(A) added in trans inhibits translation from capped poly(A)⁺ mRNAs, but stimulates translation from capped poly(A)^- mRNAs. We suggest that poly(A) is the formal equivalent of a transcriptional enhancer, i.e., that poly(A)-binding protein (PABP) bound at the 3'-end of mRNA may facilitate the binding of an initiation factor or ribosomal subunit at the mRNA 5'-end. Advisors/Committee Members: Allan Jacobson.

Subjects/Keywords: RNA; Messenger; Translation; Genetic; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides

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APA (6^th Edition):

Munroe, D. (1999). mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/67

Chicago Manual of Style (16^th Edition):

Munroe, David. “mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis.” 1999. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/67.

MLA Handbook (7^th Edition):

Munroe, David. “mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis.” 1999. Web. 08 Mar 2021.

Vancouver:

Munroe D. mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 1999. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/67.

Council of Science Editors:

Munroe D. mRNA Poly(A) tail: a 3' Enhancer of Translational Initiation: a Thesis. [Doctoral Dissertation]. U of Massachusetts : Med; 1999. Available from: https://escholarship.umassmed.edu/gsbs_diss/67

26. Satishchandran, Abhishek. The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation.

Degree: PhD, Medicine, 2016, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/838

► Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this… (more)

Subjects/Keywords: Alcoholism; Alcoholic Fatty Liver; Hepatocytes; Liver Cirrhosis; Alcoholic Liver Diseases; MicroRNAs; Cellular and Molecular Physiology; Digestive System Diseases; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Satishchandran, A. (2016). The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/838

Chicago Manual of Style (16^th Edition):

Satishchandran, Abhishek. “The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation.” 2016. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. http://escholarship.umassmed.edu/gsbs_diss/838.

MLA Handbook (7^th Edition):

Satishchandran, Abhishek. “The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation.” 2016. Web. 08 Mar 2021.

Vancouver:

Satishchandran A. The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2016. [cited 2021 Mar 08]. Available from: http://escholarship.umassmed.edu/gsbs_diss/838.

Council of Science Editors:

Satishchandran A. The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2016. Available from: http://escholarship.umassmed.edu/gsbs_diss/838

27. Quattrochi, Brian J. Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation.

Degree: PhD, Molecular, Cell and Cancer Biology Department, 2015, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/776

► Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One… (more)

Subjects/Keywords: Pancreatic Ductal Carcinoma; Carcinogenesis; Neoplastic Cell Transformation; ras Genes; MicroRNAs; Oncogenes; Proto-Oncogene Proteins; Cancer Biology; Genetics and Genomics; Neoplasms; Nucleic Acids, Nucleotides, and Nucleosides; Oncology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Quattrochi, B. J. (2015). Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/776

Chicago Manual of Style (16^th Edition):

Quattrochi, Brian J. “Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation.” 2015. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. http://escholarship.umassmed.edu/gsbs_diss/776.

MLA Handbook (7^th Edition):

Quattrochi, Brian J. “Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation.” 2015. Web. 08 Mar 2021.

Vancouver:

Quattrochi BJ. Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2015. [cited 2021 Mar 08]. Available from: http://escholarship.umassmed.edu/gsbs_diss/776.

Council of Science Editors:

Quattrochi BJ. Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2015. Available from: http://escholarship.umassmed.edu/gsbs_diss/776

28. Min, Ei Ei. Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation.

Degree: Interdisciplinary Graduate Program, Microbiology and Physiological Systems, 2015, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/780

► Nonsense-mediated mRNA decay (NMD) specifically targets mRNAs with premature translation termination codons for rapid degradation. NMD is a highly conserved translation-dependent mRNA decay pathway,… (more)

Subjects/Keywords: Nonsense Codon; Terminator Codon; Nonsense Mediated mRNA Decay; Trans-Activators; Messenger RNA; Ribosomes; Saccharomyces cerevisiae; Genetics and Genomics; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Min, E. E. (2015). Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/780

Chicago Manual of Style (16^th Edition):

Min, Ei Ei. “Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation.” 2015. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. http://escholarship.umassmed.edu/gsbs_diss/780.

MLA Handbook (7^th Edition):

Min, Ei Ei. “Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation.” 2015. Web. 08 Mar 2021.

Vancouver:

Min EE. Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2015. [cited 2021 Mar 08]. Available from: http://escholarship.umassmed.edu/gsbs_diss/780.

Council of Science Editors:

Min EE. Yeast Upf1 Associates With RibosomesTranslating mRNA Coding Sequences Upstream of Normal Termination Codons: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2015. Available from: http://escholarship.umassmed.edu/gsbs_diss/780

29. Limoncelli, Kelly A. Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq.

Degree: Neuroscience, RNA Therapeutics Institute, 2017, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/945

► The translation of mRNA into functional proteins is essential for all life. In eukaryotes, aberrant RNAs containing sequence features that stall or severely slow… (more)

Subjects/Keywords: biochemistry; deep-sequencing; neurodegenerative disease; quality control; ribosome; RNA biology; RNA damage; RNA-Seq; structural biology; translation; yeast; Biochemistry; Bioinformatics; Genetics; Molecular Biology; Nucleic Acids, Nucleotides, and Nucleosides; Structural Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Limoncelli, K. A. (2017). Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/945

Chicago Manual of Style (16^th Edition):

Limoncelli, Kelly A. “Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq.” 2017. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/945.

MLA Handbook (7^th Edition):

Limoncelli, Kelly A. “Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq.” 2017. Web. 08 Mar 2021.

Vancouver:

Limoncelli KA. Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2017. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/945.

Council of Science Editors:

Limoncelli KA. Identification of Factors Involved in 18S Nonfunctional Ribosomal RNA Decay and a Method for Detecting 8-oxoguanosine by RNA-Seq. [Doctoral Dissertation]. U of Massachusetts : Med; 2017. Available from: https://escholarship.umassmed.edu/gsbs_diss/945

30. Herrick, David. Structural Determinants of mRNA Turnover in Yeast: a Thesis.

Degree: Molecular Genetics and Microbiology, Microbiology and Physiological Systems, 1989, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/39

► Large differences exist in the decay rates of individual mRNAs yet the molecular basis for such differences is substantially unknown. We have developed a… (more)

▼ Large differences exist in the decay rates of individual mRNAs yet the molecular basis for such differences is substantially unknown. We have developed a procedure for the measurement of individual mRNAs in the yeast Saccharomyces cerevisiae which utilizes northern or dot blotting to quantitate the levels of individual mRNAs after thermal inactivation of RNA polymerase II in an rpb1-1 temperature-sensitive mutant strain (RY260). To assess the reliability of half-life measurements obtained in this manner, we have compared the results of this procedure to results obtained by three other procedures (pulse-chase analysis, approach to steady-state labeling, and inhibition of transcription with thiolutin) and also evaluated whether heat-shock alters mRNA decay rates. We find that: i) for most mRNAs, all four procedures yield comparable relative decay rates and ii) there are no significant differences in the mRNA decay rates measured in heat-shocked or non-heat-shocked cells. Of the 20 mRNAs studied, 11, including those encoded by HIS3, STE2, STE3, and MATα1, were unstable (t_1/21/2> 25 min). We have begun to assess the basis and significance of such differences in the decay rates of these two classes of mRNA. The following parameters have been analyzed to determine their role in mRNA decay: i) mRNA size; ii) poly(A) tail metabolism; iii) translational status; iv) relative content of rare codons; and v) structures and sequences within the 3'-untranslated region (UTR). To identify the structural determinants responsible for the rapid decay of the unstable HIS3 and STE2 mRNAs, recombinants of their respective genes were constructed and transformed into strain RY260 on centromere-containing vectors, and the half-lives of the resulting chimeric mRNAs were measured in vivo. Chimeric genes were constructed in which the 3'-UTR of ACT1 was replaced with the corresponding region of the unstable HIS3 or STE2 mRNAs. The decay rate of the ACT1-5'-HIS3-3' mRNA was very similiar to that of the stable endogenous ACT1 mRNA, implying that the 3'-end of HIS3 is not sufficient to transfer the instability phenotype of the HIS3 mRNA. The HIS3-5'-ACT1-3' mRNA from the reciprocal construct was unstable, suggesting that HIS3 instability determinants are located within its 5'-UTR or coding sequence. A 411 nucleotide (nt) deletion within the HIS3 coding region (with either the HIS3 or ACT1 3'-UTR) was stabilized 3-fold suggesting this region is necessary for the rapid decay of HIS3 mRNA. Insertion of these 411 nts in-frame into the entire ACT1 gene had no significant effect on the stability of the hybrid mRNA implying that these HIS3 sequences are not sufficient to function on their own and that they may have to interact with HIS3 5'- sequences. The ACT1-5' -STE2-3' hybrid mRNA decayed with an intermediate half-life of 12 min. Furthermore, an 82% deletion of the STE2 coding region increased the half-life by nearly 2-fold. Both results suggest that instability determinants of STE2 mRNA are not restricted to the 3'-UTR. Our overall… Advisors/Committee Members: Allan Jacobson.

Subjects/Keywords: Microbiology; RNA; Messenger; Saccharomyces cerevisiae; Fungi; Microbiology; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Herrick, D. (1989). Structural Determinants of mRNA Turnover in Yeast: a Thesis. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/39

Chicago Manual of Style (16^th Edition):

Herrick, David. “Structural Determinants of mRNA Turnover in Yeast: a Thesis.” 1989. Doctoral Dissertation, U of Massachusetts : Med. Accessed March 08, 2021. https://escholarship.umassmed.edu/gsbs_diss/39.

MLA Handbook (7^th Edition):

Herrick, David. “Structural Determinants of mRNA Turnover in Yeast: a Thesis.” 1989. Web. 08 Mar 2021.

Vancouver:

Herrick D. Structural Determinants of mRNA Turnover in Yeast: a Thesis. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 1989. [cited 2021 Mar 08]. Available from: https://escholarship.umassmed.edu/gsbs_diss/39.

Council of Science Editors:

Herrick D. Structural Determinants of mRNA Turnover in Yeast: a Thesis. [Doctoral Dissertation]. U of Massachusetts : Med; 1989. Available from: https://escholarship.umassmed.edu/gsbs_diss/39

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