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Vanderbilt University
1.
Wang, Dong.
Basophile: accurate fragment charge state prediction improves peptide identification rates.
Degree: MS, Biomedical Informatics, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/14397 
► In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most…
(more)
▼ In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most widely used strategy (Naïve model) is oversimplified, breaking all peptide bonds with equal probability to produce fragments of all charges below that of the precursor ion. More accurate models are too computationally intensive for on-the-fly use in database search algorithms. We created an ordinal-regression based model called Basophile that reflects the relative importance of basic residues and fragment length in charge retention during CID/HCD fragmentation of charged peptides. The model improves the accuracy of predictions by reducing the number of unnecessary fragments that are routinely predicted for highly charged precursors. When compared with the Naïve model and Protein Prospector’s prediction model, Basophile has shown an average of 26% and 28% more identifications in triply-charged precursors on ion trap data. Basophile achieves simplicity and speed by solving the prediction problem with an ordinal regression equation, which can be easily incorporated into any database search software for shotgun proteomic identification.
Advisors/Committee Members: Bing Zhang (committee member), Daniel C. Liebler (committee member), David L. Tabb (Committee Chair).
Subjects/Keywords: fragmentation; mass spectrometry; proteomics; ordinal regression
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APA (6th Edition):
Wang, D. (2012). Basophile: accurate fragment charge state prediction improves peptide identification rates. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14397
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wang, Dong. “Basophile: accurate fragment charge state prediction improves peptide identification rates.” 2012. Thesis, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14397.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wang, Dong. “Basophile: accurate fragment charge state prediction improves peptide identification rates.” 2012. Web. 19 Jan 2021.
Vancouver:
Wang D. Basophile: accurate fragment charge state prediction improves peptide identification rates. [Internet] [Thesis]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14397.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wang D. Basophile: accurate fragment charge state prediction improves peptide identification rates. [Thesis]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/14397
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
2.
Ma, Zeqiang.
Algorithms for shotgun proteomics spectral identification and quality assessment.
Degree: PhD, Biomedical Informatics, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/11036
► Tandem mass spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. Assessing the full information content of shotgun proteomics experiments has…
(more)
▼ Tandem mass spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. Assessing the full information content of shotgun proteomics experiments has motivated a series of powerful bioinformatics advances. Here I present three bioinformatics tools for shotgun proteomics spectral identification and quality assessment. The IDBoost tool is a post-identification analysis tool that rescues spectral identifications and corrects identification errors by incorporating the relationships inferred through spectral clustering. The ScanRanker tool offers a way to recover unidentified high quality spectra for additional analysis via the assessment of tandem mass spectral quality. The QuaMeter tool focuses on the quality assessment of shotgun proteomics experiments and provides objective criteria for the evaluation of analytical system variability. Each tool was developed to solve one aspect of problems but together they work coordinately to provide an improved shotgun proteomics data analysis pipeline. The source code and binaries of these tools are available from http://fenchurch.mc.
vanderbilt.edu/.
Advisors/Committee Members: Daniel C. Liebler (committee member), Bing Zhang (committee member), Kathleen L. Gould (committee member), Zhongming Zhao (committee member), David L. Tabb (Committee Chair).
Subjects/Keywords: mass spectrometry; proteomics; bioinformatics; quality assessment; quality control; peptide identification
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APA (6th Edition):
Ma, Z. (2012). Algorithms for shotgun proteomics spectral identification and quality assessment. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11036
Chicago Manual of Style (16th Edition):
Ma, Zeqiang. “Algorithms for shotgun proteomics spectral identification and quality assessment.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/11036.
MLA Handbook (7th Edition):
Ma, Zeqiang. “Algorithms for shotgun proteomics spectral identification and quality assessment.” 2012. Web. 19 Jan 2021.
Vancouver:
Ma Z. Algorithms for shotgun proteomics spectral identification and quality assessment. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/11036.
Council of Science Editors:
Ma Z. Algorithms for shotgun proteomics spectral identification and quality assessment. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/11036
Vanderbilt University
3.
Myers, Matthew V.
Proteomic Signatures of Epidermal Growth Factor Receptor Signaling.
Degree: PhD, Biochemistry, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/10475
► Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be…
(more)
▼ Analysis of cellular signaling networks typically involves targeted
measurements of phosphorylated protein intermediates. However,
phosphoproteomic analyses usually require affinity enrichment of
phosphopeptides and can be complicated by artifactual changes in
phosphorylation caused by uncontrolled preanalytical variables, particularly in
the analysis of tissue specimens. I hypothesized that changes in protein
expression, which are more stable and easily analyzed, could reflect network
stimulation and inhibition. This approach was employed to analyze stimulation
and inhibition of the epidermal growth factor receptor (EGFR) by EGF and
selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating
A431 cells, EGF-stimulated cells and cells co-treated with the EGFR inhibitors
cetuximab or gefitinib identified groups of differentially expressed proteins.
Comparisons of these protein groups identified 13 proteins whose EGF-induced
expression changes were reversed by both EGFR inhibitors. Targeted multiple-
reaction-monitoring (MRM) analysis verified differential expression of 12 of
these proteins, which comprise a candidate EGFR inhibition signature. I then
tested these 12 proteins by MRM analysis in 3 other models: 1) a comparison of
DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in
formalin-fixed, paraffin-embedded (FFPE) mouse xenograft DiFi and HCT116
tumors, and 3) in tissue biopsies from a patient with the gastric
hyperproliferative disorder Ménétrier’s disease, who was treated with cetuximab.
Of the proteins in the candidate signature, a core group, including
c-Jun,
jagged-1, and claudin 4 were decreased by EGFR inhibitors in all three models.
Although the goal of these studies was not to validate a clinically-useful EGFR
inhibition signature, the results confirm the hypothesis and outline a
prototypical approach to derive and test protein expression signatures for drug
action on signaling networks.
A secondary goal of this research was to apply a new method to quantify
protein modification changes to EGFR using internal reference peptides (IRP).
The major focus of this work was to assess the performance of this newly
developed MS-based quantitation method to detect phosphorylation changes on
EGFR by comparing the performance characteristics to stable isotope dilution
(SID) methods. Initial studies are presented along with suggestions for future
studies using overall findings in this dissertation.
Advisors/Committee Members: Jennifer Pietenpol (committee member), Carlos Arteaga (committee member), Graham Carpenter (committee member), Robert Coffey (committee member), Daniel C. Liebler (Committee Chair).
Subjects/Keywords: mass spectrometry; quantitation; proteomics; biochemistry; EGFR
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APA (6th Edition):
Myers, M. V. (2012). Proteomic Signatures of Epidermal Growth Factor Receptor Signaling. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10475
Chicago Manual of Style (16th Edition):
Myers, Matthew V. “Proteomic Signatures of Epidermal Growth Factor Receptor Signaling.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/10475.
MLA Handbook (7th Edition):
Myers, Matthew V. “Proteomic Signatures of Epidermal Growth Factor Receptor Signaling.” 2012. Web. 19 Jan 2021.
Vancouver:
Myers MV. Proteomic Signatures of Epidermal Growth Factor Receptor Signaling. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/10475.
Council of Science Editors:
Myers MV. Proteomic Signatures of Epidermal Growth Factor Receptor Signaling. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/10475
Vanderbilt University
4.
Burkewitz, Kristopher.
Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.
Degree: PhD, Pharmacology, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/12205
► Proteostasis is maintained by a complex network of genes and processes which includes core synthesis and degradation machineries as well as chemical and protein chaperones.…
(more)
▼ Proteostasis is maintained by a complex network of genes and processes which includes core synthesis and degradation machineries as well as chemical and protein chaperones. Much of what is known about the function and organization of the proteostasis network stems from analyzing how cells respond to genetic or environmental perturbation of proteomic integrity. Recent evidence points to a critical role for the proteostasis network in survival of hypertonic environments, but the proteotoxic effects of hypertonic stress remain largely undescribed. Employing the many experimental advantages of the nematode
C. elegans, we provide the first detailed description of the nature and extent of protein damage caused by hypertonic stress. Misfolding and aggregation of diverse reporters and endogenous proteins are rapid and widespread in vivo. Additionally, we demonstrate that acclimation of
C. elegans to a mild hypertonic environment activates unknown proteostasis activities capable of preventing aggregation during extreme hypertonic stress.
To define novel aspects of the hypertonic stress response and extend our understanding of cellular proteostasis strategies, we employ genetic and pharmacological approaches in determining the mechanism by which hypertonic acclimation enhances proteostasis. We hypothesize that chemical chaperones, protein chaperones, proteolysis machineries, and/or protein synthesis must be involved. Surprisingly, hypertonicity- or mutation-induced accumulation of glycerol, an organic osmolyte widely believed to act as a chemical chaperone in vivo, does not directly ameliorate protein damage during stress or aging. Protein chaperone expression is not transcriptionally upregulated. Further, hypertonic stress actually reduces protein degradation, an effect not reversed by acclimation. We demonstrate for the first time that suppression of protein translation during an environmental stress directly enhances proteostasis by preventing aggregation of extant proteins. Combined with recent observations that inhibition of translation extends lifespan and occurs naturally in response to other proteotoxic stressors, this finding suggests that translational reprogramming represents a conserved mechanism by which cells reduce the population of nascent, damage-prone proteins to enhance the availability and effectiveness of pre-existing chaperones.
Advisors/Committee Members: Dr. Richard M. Breyer (committee member), Dr. Hassane S. Mchaourab (committee member), Dr. Daniel C. Liebler (committee member), Dr. Kevin Strange (committee member), Dr. Jerod S. Denton (Committee Chair).
Subjects/Keywords: C. elegans; proteostasis; organic osmolytes; protein aggregation; osmotic stress; hypertonic stress
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APA (6th Edition):
Burkewitz, K. (2012). Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12205
Chicago Manual of Style (16th Edition):
Burkewitz, Kristopher. “Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/12205.
MLA Handbook (7th Edition):
Burkewitz, Kristopher. “Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.” 2012. Web. 19 Jan 2021.
Vancouver:
Burkewitz K. Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/12205.
Council of Science Editors:
Burkewitz K. Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/12205
Vanderbilt University
5.
Camarillo, Jeannie Marie.
Functional implications of electrophilic protein adducts.
Degree: PhD, Biochemistry, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/14578
► Oxidative stress is a contributing factor in a number of chronic diseases, including cancer, atherosclerosis, and neurodegenerative diseases. Lipid peroxidation that occurs during periods of…
(more)
▼ Oxidative stress is a contributing factor in a number of chronic diseases, including cancer, atherosclerosis, and neurodegenerative diseases. Lipid peroxidation that occurs during periods of oxidative stress and decomposition of these oxidized lipids results in the formation of lipid electrophiles. 4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are two lipid aldehydes which are generated as a result of lipid peroxidation, and both can adduct nucleophilic side chains of amino acids in proteins. A large number of protein targets have been identified for HNE and ONE, consisting of an array of adduct structures Here, we show that these adducts have distinct functional implications on the activity and regulation of the target protein. CDK2, a key cell cycle kinase which regulates the G1/S-phase transition, is adducted by HNE for up to 16 h. The adduction of CDK2 inhibits kinase activity in vitro and in cells and delays cell cycle progression into S-phase following HNE treatment. PIN1 is a cis/trans isomerase, which plays a key role in regulating of a number of cell signaling pathways. PIN1 is modified by 4-oxo-2-nonenal ONE at the active-site Cys and forms a cross-link with a nearby Lys, thereby inactivating the protein. Using site-specific incorporation of deuterium in ONE, we were able to determine a mechanism of cross-link formation and definitively show that nucleophilic attack occurs at the third carbon of ONE. Histone proteins have also been shown to be preferential targets for ONE modification, and these proteins have a direct effect on the regulation of gene expression and chromatin structure. We have developed a method to selectively isolate regions of DNA associated with these adducted histones using click-chemistry. The method, coupled with next generation DNA sequencing, termed Click-Seq, shows few regions of enrichment, suggesting that ONE broadly adducts chromatin. Furthermore, the levels of these adducts are two orders of magnitude lower than the canonical histone modifications. Together, these data show that the lipid electrophile HNE and ONE can have a significant impact on enzyme activity, alterations in cell signaling pathway, and regulation of gene expression.
Advisors/Committee Members: Jennifer A. Pietenpol (committee member), William P. Tansey (committee member), David Cortez (committee member), Lawrence J. Marnett (committee member), Daniel C. Liebler (Committee Chair).
Subjects/Keywords: hydroxynonenal; lipid peroxidation; click chemistry; lipid electrophiles; oxononenal
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APA (6th Edition):
Camarillo, J. M. (2016). Functional implications of electrophilic protein adducts. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14578
Chicago Manual of Style (16th Edition):
Camarillo, Jeannie Marie. “Functional implications of electrophilic protein adducts.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14578.
MLA Handbook (7th Edition):
Camarillo, Jeannie Marie. “Functional implications of electrophilic protein adducts.” 2016. Web. 19 Jan 2021.
Vancouver:
Camarillo JM. Functional implications of electrophilic protein adducts. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14578.
Council of Science Editors:
Camarillo JM. Functional implications of electrophilic protein adducts. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/14578
Vanderbilt University
6.
Bruntz, Ronald Chase.
Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.
Degree: PhD, Pharmacology, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/10427
► The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to…
(more)
▼ The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to generate a choline headgroup and the important lipid second messenger, phosphatidic acid (PtdOH). PLD family members are found in a diverse range of species from viruses to humans and regulate many important physiological processes including cytoskeletal rearrangements, cell migration, immune response, and cell proliferation. As such, PLD promotes oncogenic processes and elevated PLD activity has been documented in many types of cancerous tissue and derived cell lines. PLD activity is associated with cell cycle progression, resistance to apoptotic stimuli, and tumor cell invasion, but the molecular mechanisms of these PLD-mediated processes are largely uncharacterized. The goal of this project was to identify and characterize novel PLD-protein complexes in order to further understand the mechanisms by which PLD promotes cancer growth and survival. In this dissertation, PLD-derived PtdOH is demonstrated to be a novel regulator of pro-survival Akt kinase in glioblastoma cells by regulating membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. Additionally, PLD is shown to interact with a number of metabolic enzymes and a potential role for the regulation of cellular bioenergetics in GBM is explored. The results of this research provide mechanistic insight into PLD-mediated cancer cell survival.
Advisors/Committee Members: Brian E. Wadzinski (committee member), Daniel C. Liebler (committee member), H. Alex Brown (committee member), Heidi E. Hamm (committee member), Kevin C. Ess (committee member), John H. Exton (Committee Chair).
Subjects/Keywords: phospholipase D; phosphatidic acid; cancer; Akt; cell signaling; autophagy
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APA (6th Edition):
Bruntz, R. C. (2014). Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10427
Chicago Manual of Style (16th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/10427.
MLA Handbook (7th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Web. 19 Jan 2021.
Vancouver:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/10427.
Council of Science Editors:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/10427
Vanderbilt University
7.
Hutton, Josiah Ewing III.
Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.
Degree: PhD, Biochemistry, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/13946
► BIOCHEMISTRY Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer Josiah Ewing Hutton, III. Dissertation under the direction of Professor Daniel C. Liebler Analysis…
(more)
▼ BIOCHEMISTRY
Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer
Josiah Ewing Hutton, III.
Dissertation under the direction of Professor
Daniel C.
Liebler
Analysis of cancer cells that have undergone metabolic reprogramming, where glucose metabolism is altered to support rapid proliferation, is typically performed utilizing transcriptomic and metabolomic techniques. Transcriptomic data does not always accurately reflect protein expression levels, and metabolomic data alone does not sufficiently explain how these cancer cells have undergone metabolic reprogramming. Mutations in the oncogenes KRAS and BRAF induce metabolic reprogramming in colorectal cancers through enhanced glucose transport, but the broader impact of these oncogenes on metabolic pathways is unclear. I hypothesized that mutant KRAS and mutant BRAF drive metabolic reprogramming in colorectal cancer cells by diverting glucose and glutamine carbons to the production of biosynthetic precursors for rapid growth and that this metabolic reprogramming can be detected by mass spectrometry based proteomic methods. These methods were used, in conjunction with RNA-Seq and metabolite measurements, to determine if isogenic DLD-1 and isogenic RKO cell lines had undergone metabolic reprogramming driven by mutant KRAS G13D and mutant BRAF V600E, respectively. Glucose consumption and lactate production rates indicated that the isogenic cells expressing the mutant oncogenes had undergone metabolic reprogramming. The global transcriptomic and shotgun proteomic analyses did not reveal any metabolic reprogramming at the mRNA or protein levels. However, more sensitive, precise, targeted proteomic analysis of 73 metabolism proteins in these cell lines revealed biologically important protein expression fold changes in proteins involved in glucose metabolism, glutamine metabolism, and the serine biosynthesis pathways. A study of 8 KRAS wild type and 8 KRAS mutant human colon tumors confirmed the association of increased expression of glycolytic and glutamine metabolic proteins with KRAS mutations. These results demonstrate that mutant KRAS and mutant BRAF drive metabolic reprogramming through modest protein expression changes. Moreover, targeted proteomics was required to measure small protein expression differences that could not be detected by transcriptomics or shotgun proteomics. Measurement of the mutant and wild type KRAS and BRAF proteins indicated that the abundance of wild type and mutant BRAF proteins reflected the allelic composition of the RKO cells, whereas wild type and mutant KRAS protein levels did not in DLD-1 cells. Levels of mutant KRAS G13D protein did not reflect the degree of metabolic reprogramming in the DLD-1 cell lines, whereas levels of mutant BRAF V600E protein were proportional to the degree of metabolic reprogramming in the RKO cells. These results underscore the importance of performing targeted, quantitative protein measurements to evaluate the impact of oncogenic mutations.
Approved Date …
Advisors/Committee Members: Charles R. Sanders (committee member), Bruce D. Carter (committee member), Robert J. Coffey (committee member), Nicholas J. Reiter (committee member), Jamey D. Young (committee member), Daniel C. Liebler (Committee Chair).
Subjects/Keywords: parallel reaction monitoring; analytical proteomics; Warburg effect; Metabolic reprogramming; multiple reaction monitoring; colorectal cancer
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APA ·
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APA (6th Edition):
Hutton, J. E. I. (2016). Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13946
Chicago Manual of Style (16th Edition):
Hutton, Josiah Ewing III. “Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/13946.
MLA Handbook (7th Edition):
Hutton, Josiah Ewing III. “Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.” 2016. Web. 19 Jan 2021.
Vancouver:
Hutton JEI. Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/13946.
Council of Science Editors:
Hutton JEI. Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/13946
Vanderbilt University
8.
Ma, Zeqiang.
IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering.
Degree: MS, Biomedical Informatics, 2009, Vanderbilt University
URL: http://hdl.handle.net/1803/12982
► Tandem mass spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. A number of database searching algorithms have been developed to…
(more)
▼ Tandem mass spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. A number of database searching algorithms have been developed to assign peptide sequences to tandem mass spectra. Assembling the peptide identifications to proteins, however, is a challenging issue because many peptides are shared among multiple proteins. IDPicker is an open-source protein assembly tool that derives a minimum protein list from peptide identifications filtered to a specified False Discovery Rate. Here, we update IDPicker to increase confident peptide identifications by combining multiple scores produced by database search tools. By segregating peptide identifications for thresholding using both the precursor charge state and the number of tryptic termini, IDPicker retrieves more peptides for protein assembly. The new version is more robust against false positive proteins, especially in searches using multispecies databases, by requiring additional novel peptides in the parsimony process. IDPicker has been designed for incorporation in many identification workflows by the addition of a graphical user interface and the ability to read identifications from the pepXML format. These advances position IDPicker for high peptide discrimination and reliable protein assembly in large-scale proteomics studies. The source code and binaries for the latest version of IDPicker are available from http://fenchurch.mc.
vanderbilt.edu/.
Advisors/Committee Members: Daniel C. Liebler (committee member), Bing Zhang (committee member), David L. Tabb (Committee Chair).
Subjects/Keywords: parsimony; protein assembly; protein inference; false discovery rate; bioinformatics
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APA ·
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Manager
APA (6th Edition):
Ma, Z. (2009). IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12982
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ma, Zeqiang. “IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering.” 2009. Thesis, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/12982.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ma, Zeqiang. “IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering.” 2009. Web. 19 Jan 2021.
Vancouver:
Ma Z. IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering. [Internet] [Thesis]. Vanderbilt University; 2009. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/12982.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ma Z. IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering. [Thesis]. Vanderbilt University; 2009. Available from: http://hdl.handle.net/1803/12982
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
9.
Wang, Jingqi.
Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent.
Degree: PhD, Chemistry, 2009, Vanderbilt University
URL: http://hdl.handle.net/1803/14339
► As a selective apoptosis inducer, apoptolidin A was isolated from Nocardiopsis Sp. by Japanese chemists in 1997. Khosla and coworkers have demonstrated that apoptolidin A…
(more)
▼ As a selective apoptosis inducer, apoptolidin A was isolated from Nocardiopsis Sp. by Japanese chemists in 1997. Khosla and coworkers have demonstrated that apoptolidin A could inhibit the activity of mitochondrial F0F1-ATP synthase. However, in Wender’s SAR study, it was clearly pointed out that there might be a new and more relevant cellular target of apoptolidin’s biological action. The goal of this project is to identify the cellular target of apoptolidin by applying advanced proteomic technologies and molecular imaging methods. Chapter I of this dissertation described the isolation of apoptolidin A, isoapoptolidin A, three minor metabolites (apoptolidin B-D) and their biological activities. Chapter II described the previous successful synthesis of apoptolidin A and apoptolidinone A. Chapter III described the latest studies on the action mechanism of apoptolidin A and application of photo-affinity probes derived from apoptolidin A to target identification. Chapter IV described the total synthesis of three unnatural apoptolidinones, and its use in the development of a biological probe for target identification. Chapter V described the successful precursor-directed bioglycosylation of synthetic apoptolidines using whole cell apoptolidin-producing bacteria (Nocardiopsis Sp.). Chapter VI described our recent findings on apoptolidins biological effects against human lung cancer H292 cells, utilization of this cell assay for SAR studies of sugar units of apoptolidin A and future directions for apoptolidin probe syntheses guided by these biological results.
Advisors/Committee Members: Eva Harth (committee member), Daniel C. Liebler (committee member), Brian O. Bachmann (committee member), Gary A. Sulikowski (Committee Chair).
Subjects/Keywords: Target identification; Apoptosis; Apoptolidin; Apoptolidinone; Biological activity
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APA (6th Edition):
Wang, J. (2009). Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14339
Chicago Manual of Style (16th Edition):
Wang, Jingqi. “Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent.” 2009. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14339.
MLA Handbook (7th Edition):
Wang, Jingqi. “Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent.” 2009. Web. 19 Jan 2021.
Vancouver:
Wang J. Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent. [Internet] [Doctoral dissertation]. Vanderbilt University; 2009. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14339.
Council of Science Editors:
Wang J. Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent. [Doctoral Dissertation]. Vanderbilt University; 2009. Available from: http://hdl.handle.net/1803/14339
Vanderbilt University
10.
Parson, Whitney Beth.
Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry.
Degree: PhD, Biochemistry, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/13370
► Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) can provide the spatial distribution, relative abundance, and molecular identity of thousands of analytes directly from tissue sections.…
(more)
▼ Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) can provide the spatial distribution, relative abundance, and molecular identity of thousands of analytes directly from tissue sections. Due to the complex nature of tissue samples, additional analyte separation is required to increase the specificity of MALDI MS for analytes of interest. Here, the addition of a post-ionization gas-phase structural separation performed by ion mobility (IM) prior to MS is evaluated for its utility to enhance MALDI MS direct tissue analysis by (1) separating analytes of interest from other endogenous compounds, (2) simultaneously analyzing phospholipids and peptides, (3) performing simultaneous fragmentation of all ions, and (4) obtaining analyte gas-phase structural information. Current applications of MALDI IM-MS for tissue analysis as well as future research directions are provided.
Advisors/Committee Members: Daniel C. Liebler (committee member), John A. McLean (committee member), David E. Ong (committee member), David L. Tabb (committee member), Richard M. Caprioli (Committee Chair).
Subjects/Keywords: mass spectrometry; phospholipids; peptides; imaging mass spectrometry; MALDI
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APA (6th Edition):
Parson, W. B. (2010). Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13370
Chicago Manual of Style (16th Edition):
Parson, Whitney Beth. “Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/13370.
MLA Handbook (7th Edition):
Parson, Whitney Beth. “Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry.” 2010. Web. 19 Jan 2021.
Vancouver:
Parson WB. Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/13370.
Council of Science Editors:
Parson WB. Structural separations of endogenous and exogenous compounds directly from tissue sections by ion mobility – mass spectrometry. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/13370
Vanderbilt University
11.
Burnum, Kristin Elizabeth.
Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry.
Degree: PhD, Biochemistry, 2008, Vanderbilt University
URL: http://hdl.handle.net/1803/15001
► Molecular events involved in successful embryo implantation take place in defined time and space but are not generally well understood. Here for the first time,…
(more)
▼ Molecular events involved in successful embryo implantation take place in defined time and space but are not generally well understood. Here for the first time, we use MALDI Imaging Mass Spectrometry (IMS) technologies to elucidate the spatial patterning of lipids and proteins during embryo implantation and demonstrate its value in helping to understand fertility and the reproductive process. For example, our analysis clearly shows previously unknown molecular distributions of lipids over time in this system. Beyond this example, we think that the approach and the concepts illustrated in this work will be of value in various areas of biology and will be critical for understanding many biological processes.
Advisors/Committee Members: H. Alex Brown (committee member), Michael R. Waterman (committee member), Jennifer A. Pietenpol (committee member), Daniel C. Liebler (committee member), Richard M. Caprioli (Committee Chair).
Subjects/Keywords: Imaging Mass Spectrometry; Embryo Implantation
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APA (6th Edition):
Burnum, K. E. (2008). Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15001
Chicago Manual of Style (16th Edition):
Burnum, Kristin Elizabeth. “Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry.” 2008. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/15001.
MLA Handbook (7th Edition):
Burnum, Kristin Elizabeth. “Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry.” 2008. Web. 19 Jan 2021.
Vancouver:
Burnum KE. Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry. [Internet] [Doctoral dissertation]. Vanderbilt University; 2008. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/15001.
Council of Science Editors:
Burnum KE. Detecting spatial and temporal distributions of lipids and proteins during embryo implantation by MALDI Imaging Mass Spectrometry. [Doctoral Dissertation]. Vanderbilt University; 2008. Available from: http://hdl.handle.net/1803/15001
Vanderbilt University
12.
Fenn, Larissa Spell.
Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry.
Degree: PhD, Chemistry, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/12127
► Many of the diseases associated with glycoprotein variation can be more effectively treated with earlier detection substantiating the need for high-throughput methodologies for glycoconjugate characterization.…
(more)
▼ Many of the diseases associated with glycoprotein variation can be more effectively treated with earlier detection substantiating the need for high-throughput methodologies for glycoconjugate characterization. This remains particularly difficult due to heterogeneity, branching, and large size of carbohydrate moieties which makes them less amenable to conventional proteomic methods. The specific aim of this research is to develop intelligent strategies for the characterization of glycans and glycoconjugates using rapid (us to ms) structural separations by ion mobility and subsequent identification by mass spectrometry in pursuit of simultaneous glycomic, lipidomic, and proteomic characterization from complex biological samples.
Advisors/Committee Members: Prof. Daniel C. Liebler (committee member), Prof. Brian O. Bachmann (committee member), Prof. Richard N. Armstrong (committee member), Prof. John A. McLean (Committee Chair).
Subjects/Keywords: collision cross section; ion mobility; mass spectrometry; glycoproteomics; glycomics; carbohydrate
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APA (6th Edition):
Fenn, L. S. (2010). Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12127
Chicago Manual of Style (16th Edition):
Fenn, Larissa Spell. “Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/12127.
MLA Handbook (7th Edition):
Fenn, Larissa Spell. “Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry.” 2010. Web. 19 Jan 2021.
Vancouver:
Fenn LS. Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/12127.
Council of Science Editors:
Fenn LS. Detection and characterization of glycans and glycoconjugates using ion mobility-mass spectrometry. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/12127
Vanderbilt University
13.
Loecken, Elisabeth Mary.
DNA-Protein Cross-Links Induced by Bis-Electrophiles.
Degree: PhD, Biochemistry, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/12099
► Diepoxybutane is a mutagenic and carcinogenic oxidation product of the important industrial chemical and environmental contaminant butadiene. The mutagenic potential of diepoxybutane is thought to…
(more)
▼ Diepoxybutane is a mutagenic and carcinogenic oxidation product of the important industrial chemical and environmental contaminant butadiene. The mutagenic potential of diepoxybutane is thought to be due in part to its bifunctional electrophilic character. One mechanism by which bis-electrophiles can exert their toxic effects is through the induction of genotoxic and mutagenic DNA-protein or –peptide cross-links. This mechanism has been shown in systems overexpressing the DNA repair protein O6-alkylguanine DNA-alkyltransferase (AGT) or glutathione transferase and involves reactions with nucleophilic cysteine residues. The hypothesis that DNA-protein crosslink formation is a more general mechanism for genotoxicity by bis-electrophiles was investigated by screening nuclear proteins for reactivity with model monofunctional electrophiles. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was identified as a candidate due to the nucleophilicity of two cysteine residues (Cys152 and Cys246) in reaction screens with model electrophiles (Dennehy, M. K. et al. (2006) Chem. Res. Toxicol. 19, 20-29). Incubation of GAPDH with bis-electrophiles resulted in inhibition of its catalytic activity but only at high concentrations of diepoxybutane. In vitro assays indicated DNA-GAPDH crosslink formation in the presence of diepoxybutane, and bis-electrophile reactivity at Cys246 was confirmed using mass spectral analysis. In contrast to AGT, overexpression of human GAPDH in Escherichia coli did not enhance mutagenesis by diepoxybutane. The candidate proteins histones H2b and H3 were identified in screens using human liver nuclei and the bis-electrophile 1,2-dibromoethane. Incubation of these proteins with diepoxybutane resulted in DNA-protein cross-links and produced protein adducts, and DNA-histone H2b cross-links were identified (immunochemically) in E. coli cells expressing histone H2b. However, heterologous expression of histone H2b in E. coli failed to enhance bis-electrophile-induced mutagenesis, although histone H2b bound DNA with even higher affinity than AGT. The extent of DNA cross-linking of isolated histone H2b was similar to that of AGT, suggesting that differences in post-cross-linking events explain the difference in mutagenesis. In a related experiment, reactive diepoxybutane-glutathione conjugates believed to contribute to enhanced mutagenesis observed in bacterial cells overexpressing glutathione transferases were investigated. Mass spectral analysis of incubations containing purified glutathione transferase, glutathione, and diepoxybutane yielded a glutathione conjugate that retained the epoxide. Diepoxybutane also produced glutathione-DNA cross-links upon incubation.
Advisors/Committee Members: Richard N. Armstrong, Ph.D. (committee member), Carmelo Rizzo, Ph.D. (committee member), Daniel C. Liebler, Ph.D. (committee member), David L. Hachey, Ph.D. (committee member), F. Peter Guengerich, Ph.D. (Committee Chair).
Subjects/Keywords: carcinogens; bis-electrophiles; DNA damage; DNA-protein cross-links
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APA ·
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MLA ·
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CSE |
Export
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APA (6th Edition):
Loecken, E. M. (2010). DNA-Protein Cross-Links Induced by Bis-Electrophiles. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12099
Chicago Manual of Style (16th Edition):
Loecken, Elisabeth Mary. “DNA-Protein Cross-Links Induced by Bis-Electrophiles.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/12099.
MLA Handbook (7th Edition):
Loecken, Elisabeth Mary. “DNA-Protein Cross-Links Induced by Bis-Electrophiles.” 2010. Web. 19 Jan 2021.
Vancouver:
Loecken EM. DNA-Protein Cross-Links Induced by Bis-Electrophiles. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/12099.
Council of Science Editors:
Loecken EM. DNA-Protein Cross-Links Induced by Bis-Electrophiles. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/12099
. 
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