2017 UMKC Dissertations - Access Restricted to UMKC

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https://hdl.handle.net/10355/60015

The items in this collection are dissertations that are available only to members of the University of Missouri-Kansas City campus. Click on one of the browse buttons above for a complete listing of the works.

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Ferroelectric System Dynamics and the Properties of Ferroelectric / Two-Dimensional Electron Gas Heterostructures: a Ginzburg–Landau Study
(University of Missouri -- Kansas City, 2017) Richman, Michael Steven; Caruso, Anthony N.; Rulis, Paul Michael, 1976-
Understanding the electronic response of materials to applied electric fields is an outstanding goal in solid-state theory. One aspect of this goal is to accurately predict the electric polarization of certain materials and how that polarization changes the electronic structure of adjacent solids. This is motivated by applications that include next-generation field-effect transistors and other switching devices. Knowledge of the response of such devices to applied fields that extend into GHz frequencies is of particular interest so that systems can be designed to provide desired responses to such fields. By using a second-order time-dependent Ginzburg–Landau model, we simulate the dynamic polarization hysteresis behavior of a ferroelectric system subjected to a sinusoidal electric field. We examine polarization hysteresis loop structure as a function of both field amplitude and field frequency. The relationship between the latter and hysteresis loop area, i.e., hysteresis dispersion, is calculated. Previous work established that the model under consideration produces experimentally expected hysteresis dispersion in the low-frequency regime. We depart from this previous work and demonstrate that: (i) this model also produces experimentally expected hysteresis dispersion in the high-frequency regime; (ii) this dispersion implies, in agreement with experimental observations, that system relaxation is characterized by an effective characteristic time which is inversely proportional to field amplitude when the latter is sufficiently high; and (iii) the considered model predicts a symmetry-breaking transition that depends on both field frequency and field amplitude. The relationship between these field parameters and hysteresis loop structure is then further quantified by considering the Fourier transform spectra of the time series of polarization. These spectra are used to determine deforming factors that measure the frequency- and amplitude-dependent distortions of hysteresis loop structures from ellipticity. The results of this harmonic analysis agree with experimental observations, thus further validating the model. Having validated the considered model, we then employ a version of it in conjunction with: (i) a method for capturing variations in the polarization near surfaces of a ferroelectric that uses the so-called extrapolation length which was proposed by Kretschmer and Binder [Phys. Rev. B 20, 1065 (1979)]; and (ii) a treatment of graphene that was recently implemented by Kurchak et al. [Phys. Rev. Appl. 8, 024027 (2017)]. This provides a composite model that we use to predict the charge carrier densities induced in graphene layers coupled to an adjacent ferroelectric slab of LiNbO3. By comparing our results to those from density functional theory calculations that were performed by Baeumer et al. [Nat. Commun. 6, 6136 (2015)], we: (i) determine an estimate for the extrapolation length which can be used for future investigation of systems consisting of graphene deposited on LiNbO₃; and (ii) establish that the composite model may accurately predict graphene charge carrier density which results from an adjacent ferroelectric. A discussion pertaining to how our work contributes to the rational design of a system that provides passive tunable transmission of radio-frequency electromagnetic fields is provided. Moreover, we elaborate on how this work can be expanded in further pursuit of this functionality.
A Genetic Screen for Tribbles Suppressors Identifies the E3 Ubiquitin Ligase Neuralized as a Novel Target
(University of Missouri -- Kansas City, 2017) Shipman, Anna Lynn; Dobens, Leonard L.
In this dissertation, I used the Drosophila wing as a model tissue for a genetic screen to identify novel targets of Tribbles. Drosophila Tribbles is the founding member of a family of pseudokinases conserved between metazoans. Tribbles family proteins have roles in the cell cycle, insulin signaling, tissue growth and early development, and have been associated with a myriad of human diseases. In the wing, expression of tribbles by the engrailed-GAL4 driver generates a distinct visual phenotype; larger cells in the posterior of the wing and overall smaller tissue size. Co-misexpression of the known targets of Tribbles slbo (Slow Border Cells) and string suppresses the Tribbles wing phenotype. We used this observation as a tool to screen for additional Tribbles targets and from our screen we identified three E3 Ubiquitin ligases as novel interactors; Neuralized, Mindbomb1 and Parkin. Of the targets identified from the screen, we focused on Neuralized. We found that Tribbles physically bound to Neuralized in a yeast two hybrid assay and in vivo, Tribbles co misexpression in an ovarian model epithelium, the follicle cells, stabilized a tagged version of Neuralized. Neuralized has known roles in Notch signaling, and so we hypothesized that Tribbles promotes Notch signaling in the follicle cells and consistent with this, we found that both Tribbles and Neuralized turn on expression of Eyes Absent, a marker of stretch cell flattening activated by Neuralized-mediated Notch signaling.
Structural Basis for the Regulation of the Ceramide Transfer Protein
(University of Missouri -- Kansas City, 2017) Prashek, Jennifer M.; Yao, Xiaolan
Ceramide, a central intermediate in sphingolipid metabolism, is synthesized at the endoplasmic reticulum (ER) and transferred to the Golgi by the ceramide transfer (CERT) protein for conversion to sphingomyelin (SM). CERT is a multi-domain protein that contains an amino terminal pleckstrin homology (PH) domain and a carboxy terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain. PH targets CERT to the Golgi through interactions with phosphatidylinositol-4-monophosphate (PtdIns(4)P) and START carries out the transfer of ceramide. Following PH is a short serine rich (SR) motif. Phosphorylation of SR inhibits both PH and START function, but only when both are present on the same molecule, suggesting an auto-inhibitory interaction. In this study, we used biochemical and structural techniques to investigate the role of the PH and START domains and their interactions in the function and regulation of CERT. Our structural studies showed that CERT PH binds to PtdIns(4)P via the canonical ligand binding pocket of PH domains. With a better understanding of PH, we turned our focus to the PH/START interaction. Employing a combination of structural techniques, we determined that PH binds START at the same binding interface used to bind PtdIns(4)P. Consistent with the structural findings, START was shown to inhibit PH/PtdIns(4)P binding in vitro. To determine how this interaction regulates full-length CERT, we characterized the function of CERT mutants with disrupted PH/START interactions. Our results revealed that the PH/START auto-inhibitory interaction reduces the PtdIns(4)P binding, ceramide transfer activity, and Golgi localization of CERT. The results also indicated the PH/START interaction occurs in both SR phosphorylated and dephosphorylated CERT. We propose the following model for CERT regulation. The PH and START domains interact and inhibit dephosphorylated CERT until PH binding to the PtdIns(4)P-enriched Golgi disrupts the PH/START interaction. However, following SR phosphorylation, the PH/START interaction can no longer be disrupted by PtdIns(4)P binding and CERT remains inactive. Studies in this dissertation provide important insights into CERT function and regulation.
Discovery of PSMA-Specific Peptide Ligands and Development of A Noncovalent Method to Attach Chemical Moieties to siRNA
(University of Missouri -- Kansas City, 2017) Jin, Wei; Cheng, Kun (Professor)
The objective of this dissertation is to discover PSMA (Prostate Specific Membrane Antigen)-specific peptide ligands using phage display and employ peptide nucleic acid as a complementary linker to attach chemical moieties to siRNA. In Chapters 1 and 2, we introduced and discussed the background of prostate cancer chemotherapy, PSMA specific ligands for tumor imaging and targeted drug delivery, mechanism and challenge of siRNA based therapeutics, as well as the advantages and clinical applications of peptide nucleic acids (PNAs). In Chapter 3, a PSMA specific peptide ligand was identified using phage display. A novel combinatorial phage biopanning strategy was employed to identify peptide ligands, which can specifically bind to PSMA. Among all candidate peptides, GTI peptide exhibits the highest affinity and the highest specificity to PSMA protein and PSMA positive cancer cells. When it is conjugated to pro-apoptotic KLA peptide, the GTI-KLA fusion peptide be can specifically uptaken by PSMA positive LNCaP cells and induce cell apoptosis. Biodistribution studies demonstrate that GTI peptide is specifically uptakes in PSMA positive tumors and this result indicates GTI peptide has great potential to be used as a ligand for targeted drug delivery for prostate cancer therapy. In Chapter 4, in order to improve the serum stability and increase the selectivity of siRNA, peptide nucleic acids (PNAs) were employed as a complementary bridge to link siRNA and targeting moieties. After optimizing the strategy, the siRNA-PNA chimera with a 9 mer PNA sequence annealed to the 5’ end of the antisense strand of siRNA exhibits the best serum stability and comparable silencing effect to free siRNA. This siRNA-PNA chimera platform was applied to deliver PCPB2 siRNA to high IGF2R expressed HSC-T6 cells by conjugation of a peptide-431, which is a targeting moiety of IGF2R. The formulated siPCPB2-PNA-peptide-431 demonstrates significantly higher cellular uptake and good silencing effect in HSC-T6 cells. In order to further increase silencing activity, biotin, instead of peptide-431, was used to conjugate PNA and formulate siPCPB2-PNA biotin, which was then mixed with biotin-peptide-431 and neutravidin to formulate neutravidin-based nanocomplex. This nanocomplex exhibits excellent silencing activity in vitro.
Biochemical and Structural Studies of the Role of FKBP(L)s in the fly and Mammalian Circadian Cycle
(University of Missouri -- Kansas City, 2017) Agyekum, Kwaku Boadi; Bouyain, Samuel
FK506 binding-like proteins (FKBPLs) are proteins that structurally resemble the immunophilins. Their functions in cell signaling include protein folding, molecular trafficking, RNA splicing and cell cycle regulation among others. Bride of Doubletime (BDBT) previously designated as CG17282 in the flybase was identified as a circadian clock component that stimulates DBT’s circadian function. Here, we have used biochemical and structural approaches to characterize BDBT. We determined the x-ray crystal structure of BDBT and the analysis showed that it is a noncanonical FK506-binding protein with an inactive peptide prolyl-isomerase domain that interacts with DOUBLETIME and tetratricopeptide repeats at its C-terminal region that may mediate protein-protein interaction. We used similar techniques to identify BDBT vertebrate functional homologues FKBP51, FKBP52 and FKBPL. In vitro kinase assays showed that all three proteins stimulate CK1δ phosphorylation activity towards casein. Among these three proteins, FKBP51 was seen to bind mammalian casein kinase 1 delta (CK1δ) with much stronger affinity than the other FKBPs. From genetic studies, ShRNA to fkbpl in mammalian U20S cell model showed reduced amplitude and longer circadian period. Further site-directed mutagenesis revealed to us that certain residues, which are important for nuclear localization of CK1δ affect its interaction with FKBP51. Altogether, our work illustrates novel role for FKBP(L)s as molecular clock components in flies and mammals.

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