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Regulation Of Peripheral Nerve Regeneration By The Mtor Pathway, Namiko Abe
Regulation Of Peripheral Nerve Regeneration By The Mtor Pathway, Namiko Abe
All Theses and Dissertations (ETDs)
While neurons in the central nervous system: CNS) have limited capacity for regrowth after damage, neurons in the peripheral nervous system: PNS) have a robust ability to regenerate their axons following injury. Successful regeneration depends upon both extrinsic cues in the environment and the activation of intrinsic mechanisms to promote regrowth. A number of inhibitory molecules in the CNS environment that prevent axonal regrowth have been identified, but less is known regarding the signaling mechanisms that regulate regenerative ability in PNS neurons. Here, we explored multiple components of injury signaling in the PNS, including the retrograde transport of local axonal …
P38 Phoshporylates Rb On Ser567 By A Novel, Cell Cycle-Independent Mechanism That Triggers Rb-Hdm2 Interaction And Apoptosis, Rachel Delston
P38 Phoshporylates Rb On Ser567 By A Novel, Cell Cycle-Independent Mechanism That Triggers Rb-Hdm2 Interaction And Apoptosis, Rachel Delston
All Theses and Dissertations (ETDs)
The retinoblastoma protein: Rb) inhibits both cell division and apoptosis, but the mechanism by which Rb alternatively regulates these divergent outcomes remains poorly understood. Cyclin dependent kinases: Cdks) promote cell division by phosphorylating and reversibly inactivating Rb by a hierarchical series of phosphorylation events and sequential conformational changes. The stress-regulated mitogen activated protein kinase: MAPK) p38 also phosphorylates Rb, but it does so in a cell cycle-independent manner that is associated with apoptosis rather than with cell division. Here, we show that p38 phosphorylates Rb by a novel mechanism that is distinct from that of Cdks. p38 bypasses the cell …
Local And Systemic Consequences Of Reducing Notch Signaling In Skin Keratinocytes, Shadmehr Demehri
Local And Systemic Consequences Of Reducing Notch Signaling In Skin Keratinocytes, Shadmehr Demehri
All Theses and Dissertations (ETDs)
Notch is a transmembrane receptor that mediates short-range signaling between neighboring cells. Notch signaling has been implicated in various cellular and developmental processes essential in the life of metazoans. Specifically, Notch signaling plays a critical role in mammalian skin. Removal of Notch alleles in skin keratinocytes has been associated with an array of phenotypes with varying severity based on the identity and number of remaining Notch receptors. Phenotypes include carcinogenesis: in the case of Notch1 loss), transformation of hair follicles to epidermal cysts and neonatal lethality, the latter seen in the absence of all Notch signaling. Although these phenotypes were …
Analysis Of Dna-Binding Proteins In Yeast Saccharomyces Cerevisiae, Su-Wen Ho
Analysis Of Dna-Binding Proteins In Yeast Saccharomyces Cerevisiae, Su-Wen Ho
All Theses and Dissertations (ETDs)
Gene expression is an elaborate and finely tuned process involving the regulated interactions of multiple proteins with promoter and enhancer elements. A variety of approaches are currently used to study these interactions in vivo, in vitro as well as in silico. With the genome sequences of many organisms now readily available, a plethora of DNA functional elements have been predicted, but the process of identifying the proteins that bind to them in vivo remains a bottleneck. I developed two high-throughput assays to address this issue. The first is a modification of the yeast "one-hybrid" assay. The second is probing protein …
The Function And Regulation Of Senescent Stromal-Derived Osteopontin, Ermira Pazolli
The Function And Regulation Of Senescent Stromal-Derived Osteopontin, Ermira Pazolli
All Theses and Dissertations (ETDs)
Our understanding of tumors as complex organs has increased our appreciation for each component of the tumor microenvironment and its respective contribution to tumorigenesis. Fibroblasts found within a tumor actively participate in the growth, progression and metastasis of cancer cells. Senescent fibroblasts, which are permanently arrested yet metabolically active, accumulate in tissue over time where they may promote the proliferation and malignant conversion of preneoplastic cells in older individuals. I have examined the relationship between senescent fibroblasts and preneoplastic keratinocytes and identified the secreted multifunctional protein osteopontin: OPN) as a critical stromal mediating factor. RNAi-directed reduction of stromal OPN leads …
Characterization Of The Role For Nmnat, Kinase Cascades, And Purines In Axonal Degeneration, Craig Press
Characterization Of The Role For Nmnat, Kinase Cascades, And Purines In Axonal Degeneration, Craig Press
All Theses and Dissertations (ETDs)
Axonal degeneration is a prominent feature of many neurological disorders including Parkinson's disease: PD), motor neuron disease, inherited, diabetic, and drug-induced peripheral neuropathies. It is now thought that axonal degeneration is an active process, due in large part to studies of the Wlds mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury. Wlds mice have slower disease progression in numerous models of neurodegenerative diseases. The Wlds mutation results in the production of a chimeric protein that containing nicotinamide mononucleotide adenylyltransferase 1: Nmnat1). Increased expression of Nmnat isoforms are sufficient for axonal protection in vitro and in vivo. …
Role Of The Ajuba Lim Proteins In Epithelial Growth Regulation, Meghna Das Thakur
Role Of The Ajuba Lim Proteins In Epithelial Growth Regulation, Meghna Das Thakur
All Theses and Dissertations (ETDs)
The mammalian Ajuba LIM proteins: Ajuba, LIMD1, WTIP) are cytosolic adapter proteins recruited to nascent epithelial adherens junctions, where they are thought to contribute to junctional assembly and/or stability. They also shuttle into the nucleus acting as corepressors of the Snail family of transcriptional repressors, thereby contributing to epithelial mesenchymal transition. As such they have the potential to communicate cell adhesive events with nuclear responses to remodel epithelia. Determining their role(s) in vivo, however, has been challenging due to shared interacting proteins, overlapping tissue expression and functional redundancy in cells. Thus, we turned to the Drosophila model system where a …
Mechanisms Of Copper Deficiency In The Zebrafish Embryo, Erik Madsen
Mechanisms Of Copper Deficiency In The Zebrafish Embryo, Erik Madsen
All Theses and Dissertations (ETDs)
Proper maternal nutrition is critical for early embryonic development. Despite overwhelming epidemiologic data indicating the benefits nutrient supplementation for the developing organism we do not fully understand the genetics of predisposition to abnormal developmental phenotypes when faced with suboptimal nutrient levels. Copper is an essential nutrient required for critical biochemical processes. Severe defects in copper homeostasis lead to significant disease typified by the X-linked recessive disorder Menkes disease. Patients with Menkes disease have cutis laxa, bone deformities, hypopigmentation, arterial malformation, and neurodegeneration due to copper deficiency caused by loss-of-function mutations in ATP7A, a copper transport protein. Despite the critical requirement …
Engineering The Optical Properties Of Gold Nanostructures For Biomedical Applications, Leslie Au
Engineering The Optical Properties Of Gold Nanostructures For Biomedical Applications, Leslie Au
All Theses and Dissertations (ETDs)
This research investigated the synthesis and optical properties of Au nanostructures with an aim to use them as imaging agents and photothermal transducers for the diagnosis and treatment of cancer. I have produced Au nanocages with hollow interiors and porous walls using the galvanic replacement reaction between Ag nanocubes and AuCl4-. I have engineered these Au nanocages to have localized surface plasmon resonance: LSPR) peaks in the near-infrared region with strong absorption. These optical properties allow for the imaging of biological tissues at deeper penetration and the photoablation of cancer. By replacing AuCl4- with AuCl2 …
In Vivo Function Of Otopetrin 1 In The Vestibular Sensory Epithelium, Euysoo Kim
In Vivo Function Of Otopetrin 1 In The Vestibular Sensory Epithelium, Euysoo Kim
All Theses and Dissertations (ETDs)
Otopetrin family genes encode multi-transmembrane domain proteins with three highly conserved domains. In mice, three Otopetrin paralogues are found. One of its members, Otopetrin 1: Otop1) has been previously shown to be essential for the formation of otoconia in the vestibular system of the inner ear. Otoconia are calcium carbonate biominerals that are required for normal balance and the sensation of linear acceleration with respect to gravity. The mechanism by which OTOP1 mediates otoconia biosynthesis is not known, but the ability of OTOP1 to modulate [Ca2+]i in response to purinergic signals in heterologous systems suggest that OTOP1 may be involved …
Flap Endonuclease 1 Ensures Telomere Replication And Stability, Abhishek Saharia
Flap Endonuclease 1 Ensures Telomere Replication And Stability, Abhishek Saharia
All Theses and Dissertations (ETDs)
Telomeres, protein-DNA structures that distinguish the end of a chromosome from a bona fide DNA double strand break, are integral to genomic stability. High fidelity replication of telomeres is indispensable for their stability. Telomere replication is a challenging task that is completed through the coordinated actions of telomere binding proteins and DNA replication and repair proteins in ways that are not well understood. This work focuses on delineating the function of one DNA replication and repair protein, Flap Endonulcease 1: FEN1), in telomere replication and maintenance. I demonstrate that FEN1 is essential for the efficient replication of telomeres through its …
Role And Regulation Of Escrt-Iii In Multivesiculr Body Biogenesis, Soomin Shim
Role And Regulation Of Escrt-Iii In Multivesiculr Body Biogenesis, Soomin Shim
All Theses and Dissertations (ETDs)
Endosomal sorting complex required for transports: ESCRT) machinery responsible for multivesicular body: MVB) biogenesis is essential for receptor downregulation, viral budding and cytokinesis. ESCRT-III is a large polymer built from related ESCRT-III proteins that is thought to help generate intralumenal vesicles: ILVs) within the MVB. How ESCRT-III functions is poorly understood. Although ESCRT-III assembles on the endosomal membrane, its components are predominantly soluble in the cytoplasm. I found that the transition between these two states is controlled by autoinhibitory domains within ESCRT-III proteins, which I identified by structure/ function analysis in four human ESCRT-III proteins - Charged multivesicular body protein2A: …
Systemic Levels Of G-Csf And Il-6 Determine The Angiogenic Potential Of Bone Marrow Resident Monocytes, Alyssa Gregory
Systemic Levels Of G-Csf And Il-6 Determine The Angiogenic Potential Of Bone Marrow Resident Monocytes, Alyssa Gregory
All Theses and Dissertations (ETDs)
Recent studies have demonstrated the efficacy of hematopoietic cell-based therapies in promoting therapeutic angiogenesis for a wide variety of vascular syndromes, however the cell populations responsible and the mechanisms involved are poorly understood. Using a mouse model of hindlimb ischemia, we previously showed that an adoptive transfer of donor monocytes significantly enhanced revascularization. Monocytes are a widely heterogeneous cell population and differences in the ability of various monocyte subsets to mediate revascularization have not been previously investigated. Using the hindlimb ischemia model we demonstrate that an adoptive transfer of inflammatory: CX3CR loGr-1+), but not resident: CX3CR1hiGr-1-) monocytes, significantly enhances revascularization …
Coordinate Interstitial Deletions Of Retinoblastoma (Rb1) And Neurobeachin (Nbea) Genes On Chromosome 13 In Mgus And Multiple Myeloma, Julie O'Neal
All Theses and Dissertations (ETDs)
ABSTRACT OF THE DISSERTATION Coordinate interstitial deletions of Retinoblastoma: RB1) and Neurobeachin: NBEA) genes on chromosome 13 in monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma By Julie O'Neal Doctor of Philosophy in Biology and Biomedical Sciences: Molecular and Cellular Biology) Washington University in Saint Louis, 2009 Assistant Professor Michael H. Tomasson, Chair Numeric or structural chromosomal abnormalities are detected in nearly all patients with plasma cell dyscrasias, including primary amyloidosis, monoclonal gammopathy of undetermined significance: MGUS) and multiple myeloma: MM). Chromosome 13 deletions, most frequently monosomy 13, are detected in 10- 20% of MM cases by routine cytogenetics …
A Phenotypic And Genetic Characterization Of The Cell Adhesion Molecules Echinoid And Friend-Of-Echinoid In The Directed Cell Movements Of Ommatidial Rotation During Drosophila Eye Development., Jennifer Fetting
All Theses and Dissertations (ETDs)
Correct development of multicellular organisms relies on the precise patterning of cells, which must respond to and interpret specific cues that instruct the cells to differentiate and often undergo directed cell movements and rearrangements to give rise to functional tissues and organs. Differential adhesion between the stationary and mobile cells permits and promotes these cellular movements, effecting patterning of cells and tissues. During Drosophila eye development, groups of cells, the ommatidial precursors, undergo a 90° rotational movement within a matrix of stationary cells, providing the cell motility readout of tissue polarity. The mechanisms that regulate ommatidial rotation are not well …
Aggregation & Localization Of A Disease-Associated Prion Protein (Prp) Mutant, Andrea Rhonda Medrano
Aggregation & Localization Of A Disease-Associated Prion Protein (Prp) Mutant, Andrea Rhonda Medrano
All Theses and Dissertations (ETDs)
ABSTRACT OF THE DISSERTATION Aggregation & Localization of a Disease-Associated Prion Protein: PrP) Mutant by Andrea Rhonda Zaragoza Medrano Doctor of Philosophy in Biology and Biomedical Sciences: Genetics) Washington University in St. Louis, 2009 Professor David A. Harris, Chairperson Prion protein: PrP) is a GPI-anchored sialoglycoprotein involved in the pathogenesis of infectious and inherited forms of transmissible spongiform encephalopathies: TSEs). A nine-octapeptide insertional mutation in the prion protein: PrP) causes a fatal neurodegenerative disorder in both humans and transgenic mice. To determine the precise cellular localization of this mutant PrP: designated PG14), we have generated transgenic mice expressing PG14-EGFP, a …
Characterization Of Ligand-Induced Conformational Changes In The Egf Receptor, Katherine Yang
Characterization Of Ligand-Induced Conformational Changes In The Egf Receptor, Katherine Yang
All Theses and Dissertations (ETDs)
ABSTRACT OF DISSERTATION Characterization of ligand-induced conformational changes in the EGF receptor by Katherine S. Yang Doctor of Philosophy in Biochemistry Washington University in St. Louis, 2009 Professor Linda Pike, Chairperson The epidermal growth factor: EGF) receptor is a classical receptor tyrosine kinase that mediates cellular processes such as proliferation, migration, and differentiation in response to growth factor stimulation. Crystal structures of the EGF receptor suggest that its activation is associated with extensive conformational changes in both the extracellular and intracellular domains. However, evidence of these structural dynamics in intact cells has been lacking. This thesis describes the characterization of …
Targeting The Dimerization Of Erbb Receptor Tyrosine Kinases, Rob Yang
Targeting The Dimerization Of Erbb Receptor Tyrosine Kinases, Rob Yang
All Theses and Dissertations (ETDs)
The epidermal growth factor receptor: EGFR) is a membrane receptor tyrosine kinase whose over-activation has been implicated to cause many human cancers. Novel strategies to inhibit the activation of EGF receptors other than the conventional antibody-based and tyrosine kinase inhibitors are virtually non-existent but could provide benefits both in the laboratory and clinical settings. In an effort to expand the current approaches, this thesis focused on targeting the homodimerization of the EGF receptors themselves and the heterodimerization of EGF receptors with the related ErbB2 receptor. Three sub-projects were completed in the process. The first project explored the feasibility of inhibiting …
Regulation Of Bax/Bak-Dependent Cell Death Program, Hyungjin Kim
Regulation Of Bax/Bak-Dependent Cell Death Program, Hyungjin Kim
All Theses and Dissertations (ETDs)
Mammals have evolved an intricate regulation of a genetically programmed apoptotic cell death that involves mitochondria. Diverse apoptotic signals converge on mitochondria, which causes the release of cytochrome c into the cytosol to activate Apaf-1. This initiates caspase activation, which results in irreversible cellular demise. The BCL-2 family proteins constitute a critical checkpoint in mitochondrion-dependent apoptosis. Multidomain proapoptotic BAX/BAK promotes mitochondrial outer membrane permeabilization, whereas anti-apoptotic BCL-2/BCL-XL/MCL-1 protects mitochondrial integrity and prevents cytochrome c release. The proapoptotic activity of BAX/BAK is triggered by BH3-only molecules: BH3s) which are upregulated by upstream death signals. However, how these subfamilies interact …
Runx1 In Primitive Hematopoiesis And Characterization Of Hematopoietic Stem Cells In A Mouse Chronic Inflammatory Arthritis Model, Yunglin Ma
All Theses and Dissertations (ETDs)
Hematopoietic cells are essential for growth and survival throughout adult life. Two different aspects of hematopoiesis are addressed in this dissertation. I. The regulation of primitive hematopoiesis by Runx1 and TGF-beta signaling. Primitive hematopoiesis, occurring exclusively in the yolk sac, is characterized by its transient nature. As the primitive hematopoiesis declines in the yolk sac, definitive hematopoietic progenitors generated in the yolk sac and/or embryo take over in blood cell production. Whether the transition from primitive to definitive hematopoietic program reflects a mere shift in hematopoietic sites or whether it is an actively regulated process is currently unknown. Runx1 is …
Calling Cards For Dna-Binding Proteins, Haoyi Wang
Calling Cards For Dna-Binding Proteins, Haoyi Wang
All Theses and Dissertations (ETDs)
Organisms respond to their environment by altering patterns of gene expression. This process is orchestrated by transcription factors, which bind to specific DNA sequences near genes. In order to understand the regulatory networks that control transcription, the genomic targets of all transcription factors under various conditions and in different cell types must be identified. This remains a distant goal, mainly due to the lack of a high-throughput, in vivo method to study protein-DNA interactions. To fill this gap, I developed transposon "Calling Cards" for DNA-binding proteins. I endowed DNA binding proteins with the ability to direct the insertion of a …
Hiv-1 Envelope-Induced Signaling Mediates Actin Cytoskeleton Rearrangements Necessary For Fusion And Entry, Brooke Harmon
Hiv-1 Envelope-Induced Signaling Mediates Actin Cytoskeleton Rearrangements Necessary For Fusion And Entry, Brooke Harmon
All Theses and Dissertations (ETDs)
Human immunodeficiency virus type-1: HIV-1) initiates infection by direct fusion of the virus membrane with the plasma membrane of the target cell. This fusion event is a multi-step process mediated by the envelope: Env) surface subunit gp120 and the transmembrane subunit gp41 which anchors gp120 into the viral membrane. First the surface subunit gp120 binds to the primary receptor CD4. This interaction promotes actin cytoskeletal rearrangements in the target membrane that bring the chemokine coreceptor, CCR5 or CXCR4, into close proximity for binding and induces conformational changes in gp120 that allow it to couple to the coreceptor. Formation of the …