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Mechanisms Of Endocytic Sorting: A Dissertation, Deborah Marie Leonard Dec 2006

Mechanisms Of Endocytic Sorting: A Dissertation, Deborah Marie Leonard

GSBS Dissertations and Theses

Endocytosis is important for the regulation of signal transduction and for the movement of essential cellular components from outside the cell to their appropriate intracellular compartment(s). Two established mechanisms of endocytosis are clathrinmediated (CME) and clathrin-independent endocytosis, and they are responsible for internalization of different ligands. In this study, the newly established technique of total internal reflection fluorescent microscopy (TIRF-M) was used, along with standard biochemical and molecular biological tools, to systematically study the sorting and early trafficking of two established ligands of endocytosis, transferrin (Tf) and epidermal growth factor (EGF).

TIRF-M studies revealed that Tf binds its receptor ...


Quantitative Analysis Of Hedgehog Gradient Formation Using An Inducible Expression System: A Dissertation, Vivian F. Su Nov 2006

Quantitative Analysis Of Hedgehog Gradient Formation Using An Inducible Expression System: A Dissertation, Vivian F. Su

GSBS Dissertations and Theses

The Hedgehog (Hh) family of proteins are secreted growth factors that play an essential role in the embryonic development of all organisms and the main components in the pathway are conserved from insects to humans. These proteins affect patterning and morphogenesis of multiple tissues. Therefore, mutations in the Hh pathway can result in a wide range of developmental defects and oncogenic diseases. Because the main components in the pathway are conserved from insects to humans, Drosophilahas been shown to provide a genetically tractable system to gain insight into the processes that Hh is involved in.

In this study, the ...


M1 Muscarinic Modulation Of N-Type Calcium Channels: A Dissertation, John F. Heneghan Nov 2006

M1 Muscarinic Modulation Of N-Type Calcium Channels: A Dissertation, John F. Heneghan

GSBS Dissertations and Theses

The influx of calcium through N-type calcium channels (N-current) affects a myriad of neuronal functions. These include the triggering of synaptic release of neurotransmitter, adjustment of membrane potential and changes in gene transcription. N-channels are highly modulated proteins, so that N-current is attenuated or potentiated in response to environmental changes. In turn, the modulation of N-current has a direct effect on the downstream events, making the N-channel a focal point in neural signaling, and its modulation a mechanism for short term plasticity.

The modulation of N-current by M1 muscarinic receptors (M1Rs) is of particular interest for several ...


Rna Silencing Pathways In Schizosaccharomyces Pombe And Drosophila Melanogaster: A Dissertation, Alla A. Sigova Nov 2006

Rna Silencing Pathways In Schizosaccharomyces Pombe And Drosophila Melanogaster: A Dissertation, Alla A. Sigova

GSBS Dissertations and Theses

RNA silencing is an evolutionary conserved sequence-specific mechanism of regulation of gene expression. RNA interference (RNAi), a type of RNA silencing in animals, is based on recognition and endonucleolytic cleavage of target mRNA complimentary in sequence to 21-nucleotide (nt) small RNA guides, called small interfering RNAs (siRNAs). Another class of 21-nt small RNAs, called micro RNAs (miRNAs), is endogenously encoded in eukaryotic genomes. Both production of siRNAs from long double-stranded RNA (dsRNA) and biogenesis of miRNAs from hairpin structures are governed by the ribonuclease III enzyme Dicer. Although produced as duplex molecules, siRNAs and miRNAs are assembled into effector complex ...


Requirements For Assembly And Release Of Newcastle Disease Virus-Like Particles: A Dissertation, Homer Dadios Pantua Oct 2006

Requirements For Assembly And Release Of Newcastle Disease Virus-Like Particles: A Dissertation, Homer Dadios Pantua

GSBS Dissertations and Theses

The final step of paramyxovirus infection requires the assembly of viral structural components at the plasma membrane of infected cells followed by budding of virions. While the matrix (M) protein of some paramyxoviruses has been suggested to play a central role in the assembly and release of virus particles, the specific viral and host protein requirements are still unclear. Using Newcastle disease virus (NDV) as a prototype paramyxovirus, we explored the role of each of the NDV structural proteins in virion assembly and release. For these studies, we established a virus-like particle (VLP) system for NDV. The key viral proteins ...


Ifn-Α/Β Induction By Dsrna And Toll-Like Receptors Shortens Allograft Survival Induced By Costimulation Blockade: A Dissertation, Thomas B. Thornley Oct 2006

Ifn-Α/Β Induction By Dsrna And Toll-Like Receptors Shortens Allograft Survival Induced By Costimulation Blockade: A Dissertation, Thomas B. Thornley

GSBS Dissertations and Theses

Costimulation blockade protocols are promising alternatives to the use of chronic immunosuppression for promoting long-term allograft survival. However, the efficacy of costimulation blockade-based protocols is decreased by environmental insults such as viral infections. For example, lymphocytic choriomeningitis virus (LCMV) infection at the time of costimulation blockade treatment abrogates skin allograft survival in mice. In this dissertation, we test the hypothesis that viruses shorten allograft survival by activating the innate immune system through pattern-recognition receptors (PRRs), such as toll-like receptors (TLRs).

To investigate the role of innate immunity in shortening allograft survival, costimulation blockade-treated mice were co-injected with TLR2 (Pam3 ...


Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam Oct 2006

Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam

GSBS Dissertations and Theses

The generation of memory T cells following primary exposure to a pathogen is a critical feature of the vertebrate immune system which has evolved as a protective mechanism in order to defend the host against repeated assaults by the patnogen. Memory T cells are long-lived, undergo rapid proliferation upon re-activation, mediate a robust secondary response and clear the pathogen much more efficiently. These aspects have made the generation of memory T cells an attractive goal for the production of both prophylactic and therapeutic vaccines. However, the degeneracy of the T cell receptor, whereby a given T cell recognizes more than ...


Identification Of Novel (RNai DeFicient) Genes In C. Elegans: A Dissertation, Chun-Chieh G. Chen Sep 2006

Identification Of Novel (RNai DeFicient) Genes In C. Elegans: A Dissertation, Chun-Chieh G. Chen

GSBS Dissertations and Theses

RNA interference or RNAi was first discovered as an experimental approach that induces potent sequence-specific gene silencing. Remarkably, subsequent studies on dissecting the molecular mechanism of the RNAi pathway reveal that RNAi is conserved in most eukaryotes. In addition, genes and mechanisms related to RNAi are employed to elicit the regulation of endogenous gene expression that controls a variety of important biological processes. To investigate the mechanism of RNAi in the nematode C. elegans, we performed genetic screens in search of RNAi deficient mutants (rde). Here I report the summary of the genetic screens in search of rde ...


Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki Sep 2006

Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki

GSBS Dissertations and Theses

How proteins undergo conformational changes to bind a ligand is one of the most fundamental questions of protein biology. MD simulations provide a useful computational tool for studying the theoretical movements of protein in solution on nanosecond timescales. The results of these simulations can be used to guide experimental design. By correlating the theoretical models with the results of experimental studies, we can obtain a significant amount of information about protein dynamics. This study represents the application of both computational and traditional experimental techniques to study protein dynamics in HIV-1 protease. The results provide a novel mechanism for the conformational ...


Light Intermediate Chain 1: A Multifunctional Cargo Binder For Cytoplasmic Dynein 1: A Dissertation, Thomas Wadzinski Sep 2006

Light Intermediate Chain 1: A Multifunctional Cargo Binder For Cytoplasmic Dynein 1: A Dissertation, Thomas Wadzinski

GSBS Dissertations and Theses

Cells as dynamic, interactive, and self contained units of life have a need for molecular motors that can create physical forces to move cargoes within the cell. Cytoplasmic dynein 1 is one such molecular motor that has many functions in the cell. The number and variety of functions that involve cytoplasmic dynein 1 suggest that there are a number of different binding sites on dynein for different proteins. Cytoplasmic dynein 1 is a multiprotein complex made up of six different subunit families. The many different combinations of subunits that could be used to make up a cytoplasmic dynein 1 holocomplex ...


Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways: A Dissertation, Sarah R. Oikemus Sep 2006

Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways: A Dissertation, Sarah R. Oikemus

GSBS Dissertations and Theses

Several aspects of Drosophila telomere biology indicate that telomere protection can be regulated by an epigenetic mechanism. First, terminally deleted chromosomes can be stably inherited and do not induce damage responses such as apoptosis or cell cycle arrest. Second, the telomere protection proteins HP1 and HOAP localize normally to these chromosomes and protect them from fusions. Third, unprotected telomeres still contain HeT-A sequences at sites of fusions. Taken together these observations support a model in which an epigenetic mechanism mediated by DNA damage response proteins protects Drosophilatelomeres from fusion.

Work presented in this thesis demonstrates that the Drosophila proteins ...


Genetic Dissection Of The Neural Circuitry Underlying Memory Stability In Drosophila: A Dissertation, Alex Carl Keene Aug 2006

Genetic Dissection Of The Neural Circuitry Underlying Memory Stability In Drosophila: A Dissertation, Alex Carl Keene

GSBS Dissertations and Theses

Understanding how memory is formed requires looking beyond the genes involved to the neural circuitry and temporal aspects of memory. In this dissertation I have focused my investigation on Dorsal Paired Medial (DPM) neurons, two modulatory neurons essential for memory in Drosophila. DPM neurons highly express the amnesiac (amn) gene, which encodes for a putative pre-pro-neuropeptide. amn function in DPM neurons is required for memory. Here I provide evidence that DPM neurons are cholinergic and that acetylcholine (ACh) and AMN act as co-transmitters essential for DPM function. In order to investigate the temporal requirements of DPM output I blocked transmitter ...


Perturbation And Modulation Of Microtubule Cytoskeletal Elements In Response To The Potentially Oncogenic Molecules, Survivin And P53, And Cytokinesis: A Dissertation, Jack Rosa Jul 2006

Perturbation And Modulation Of Microtubule Cytoskeletal Elements In Response To The Potentially Oncogenic Molecules, Survivin And P53, And Cytokinesis: A Dissertation, Jack Rosa

GSBS Dissertations and Theses

A complex network of protein filaments collectively known as the cytoskeleton carries out several crucial cellular processes. These functions include, but are not limited to, motility, cell shape, mitosis and organelle trafficking. The cytoskeleton is also highly responsive, allowing the cell to alter its shape in response to its immediate needs and environment. One of the major components of the cytoskeleton is the microtubule network. To refer to the array of micro tubules in the cell as a skeleton is a misnomer. Microtubules, by virtue of their structure and nature, are highly dynamic, continuously growing and shrinking. They also bind ...


Development Of Pharmacological Magnetic Resonance Imaging Methods And Their Application To The Investigation Of Antipsychotic Drugs: A Dissertation, Karl F. Schmidt Jul 2006

Development Of Pharmacological Magnetic Resonance Imaging Methods And Their Application To The Investigation Of Antipsychotic Drugs: A Dissertation, Karl F. Schmidt

GSBS Dissertations and Theses

Pharmacological magnetic resonance imaging (phMRI) is the use of functional MRI techniques to elucidate the effects that psychotropic drugs have on neural activity within the brain; it is an emerging field of research that holds great potential for the investigation of drugs that act on the central nervous system by revealing the changes in neural activity that mediate observable changes in behavior, cognition, and perception. However, the realization of this potential is hampered by several unanswered questions: Are the MRI measurements reliable surrogates of changing neural activity in the presence of pharmacological agents? Is it relevant to investigate psychiatric phenomena ...


Plagl2 Cooperates In Leukemia Development By Upregulating Mpl Expression: A Dissertation, Sean F. Landrette Jun 2006

Plagl2 Cooperates In Leukemia Development By Upregulating Mpl Expression: A Dissertation, Sean F. Landrette

GSBS Dissertations and Theses

Chromosomal alterations involving the RUNXI or CBFB genes are specifically and recurrently associated with human acute myeloid leukemia (AML). One such chromosomal alteration, a pericentric inversion of chromosome 16, is present in the majority of cases of the AML subtype M4Eo. This inversion joins CBFB with the smooth muscle myosin gene MYH11 creating the fusion CBFB-MYH11. Knock-in studies in the mouse have demonstrated that expression of the protein product of the Cbfb-MYH11fusion, Cbfβ-SMMHC, predisposes mice to AML and that chemical mutagenesis both accelerates and increases the penetrance of the disease (Castilla et al., 1999). However, the mechanism of transformation ...


Regulation Of Contractility By Adenosine A1 And A2a Receptors In The Murine Heart: Role Of Protein Phosphatase 2a: A Dissertation, Eugene I. Tikh Jun 2006

Regulation Of Contractility By Adenosine A1 And A2a Receptors In The Murine Heart: Role Of Protein Phosphatase 2a: A Dissertation, Eugene I. Tikh

GSBS Dissertations and Theses

Adenosine is a nucleoside that plays an important role in the regulation of contractility in the heart. Adenosine receptors are G-protein coupled and those implicated in regulation of contractility are presumed to act via modulating the activity of adenylyl cyclase and cAMP content of cardiomyocytes. Adenosine A1 receptors (A1R) reduce the contractile response of the myocardium to β-adrenergic stimulation. This is known as anti adrenergic action. The A2A adenosine receptor (A2AR) has the opposite effect of increasing contractile responsiveness of the myocardium. The A2AR also appears to attenuate the effects of A ...


Analysis Of Toll-Like Receptor 4 Signal Transduction And Irf3 Activation In The Innate Immune Response: A Dissertation, Daniel C. Rowe Jun 2006

Analysis Of Toll-Like Receptor 4 Signal Transduction And Irf3 Activation In The Innate Immune Response: A Dissertation, Daniel C. Rowe

GSBS Dissertations and Theses

Over the last decade, the innate immune system has been the subject of extensive research. Often overlooked by the robustness and specificity of the adaptive immune system, the innate immune system is proving to be just as complex. The identification of several families of pattern recognition receptors (PRRs) has revealed an ancient yet multifaceted system of proteins that are responsible for initiating host defense. A wide array of pathogens, from virus to bacteria, is detected using this assortment of receptors. One such family, the Toll-like receptors (TLRs), has been at the forefront of this research. To date, 10 TLRs have ...


Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar May 2006

Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar

GSBS Dissertations and Theses

Mature αβ and γδ T cells arise from a common precursor population in the thymus. Much debate has focused on the mechanism of T cell lineage choice made by these multi-potential precursor cells. It is widely believed that the decision of these precursor cells to commit to the γδ or αβ T cell lineages is regulated primarily by a specific instructive signal relayed through the appropriate T cell receptor. Contrary to this model, we present evidence for a TCR-independent lineage commitment process. Comparison of global gene expression profiles from immature αβ and γδ lineage thymocytes identified Sox13, an HMG-box transcription ...


Characterization Of The Relationship Between Measles Virus Fusion, Receptor Binding, And The Virus-Specific Interaction Between The Hemagglutinin And Fusion Glycoproteins: A Dissertation, Elizabeth Ann Corey May 2006

Characterization Of The Relationship Between Measles Virus Fusion, Receptor Binding, And The Virus-Specific Interaction Between The Hemagglutinin And Fusion Glycoproteins: A Dissertation, Elizabeth Ann Corey

GSBS Dissertations and Theses

Measles (MV) virions, like those of other enveloped viruses, enter cells by fusing their lipid membranes with those of the target host cells. Additionally, infected tissues often possess giant multinucleate cells, known as syncytia, which are formed by fusion of infected cells with uninfected neighbors. Expression of both the MV attachment (H) and fusion (F) proteins is required for membrane fusion. MV H mediates receptor binding in order to bring the two membranes into close proximity prior to F activation and is thought to trigger F activation through a specific interaction between the two proteins.

Although measles H and F ...


Rb Inactivation Leads To E2f1-Mediated Dna Double Strand Break Accumulation: A Dissertation, Mary Theresa Pickering Apr 2006

Rb Inactivation Leads To E2f1-Mediated Dna Double Strand Break Accumulation: A Dissertation, Mary Theresa Pickering

GSBS Dissertations and Theses

Although it is unclear which cellular factor(s) is responsible for the genetic instability associated with initiating and sustaining cell transformation, it is known that most, if not all, cancers have mutations that inactivate the Rb-mediated growth control pathway. We show here that acute inactivation of Rb by RNA interference or expression of the E7 viral oncoprotein from human papillomavirus (HPV), and the resultant deregulation of one E2F family member, E2F1, leads to DNA double strand break (DSB) accumulation. These DSBs occur independent of apoptosis induction, and activation of ATM, NBS1, p53, or MAD2, and generation of reactive oxygen species ...


Transcriptional Regulation During Adipocyte Differentiation: A Role For Swi/Snf Chromatin Remodeling Enzymes: A Dissertation, Nunciada Salma Mar 2006

Transcriptional Regulation During Adipocyte Differentiation: A Role For Swi/Snf Chromatin Remodeling Enzymes: A Dissertation, Nunciada Salma

GSBS Dissertations and Theses

Chromatin has a compact organization in which most DNA sequences are structurally inaccessible and functionally inactive. Reconfiguration of thechromatir required to activate transcription. This reconfiguration is achieved by the action of enzymes that covalently modify nucleosomal core histones, and by enzymes that disrupt histone-DNA interactions via ATP hydrolysis.

TheSWI/SNF family of ATP-dependent chromatin remodeling enzymes has been implicated not only in gene activation but also in numerous cellular processes including differentiation, gene repression, cell cycle control, recombination and DNA repair. PPARγ, C/EBPα and C/EBPβ are transcription factors with well established roles in adipogenesis. Ectopical expression of each ...


Dissecting The Mechanism For The Selective Induction Of Apoptosis In Transformed Cells By Cav Apoptin: A Dissertation, Destin W. Heilman Mar 2006

Dissecting The Mechanism For The Selective Induction Of Apoptosis In Transformed Cells By Cav Apoptin: A Dissertation, Destin W. Heilman

GSBS Dissertations and Theses

Most existing chemotherapeutics lack adequate specificity for transformed cells and therefore have high rates of collateral damage to normal tissue. Moreover, such therapies often depend on p53 to induce cell death and are ineffective on the large number of human cancers that have lost p53 function. The discovery of novel p53-independent cancer therapies is therefore of significant interest. The Chicken Anemia Virus protein Apoptin selectively induces apoptosis in transformed cells in a p53-independent manner while leaving normal primary cells unaffected. This selectivity is thought to be largely due to cell type-specific localization: in primary cells Apoptin is cytoplasmic, whereas in ...


Human Rad51: Regulation Of Cellular Localization And Function In Response To Dna Damage: A Dissertation, Brian Thomas Bennett Feb 2006

Human Rad51: Regulation Of Cellular Localization And Function In Response To Dna Damage: A Dissertation, Brian Thomas Bennett

GSBS Dissertations and Theses

Repair of DNA double-strand breaks via homologous recombination is an essential pathway for vertebrate cell development and maintenance of genome integrity throughout the organism’s lifetime. The Rad51 enzyme provides the central catalytic function of homologous recombination while many other proteins are involved in regulation and assistance of Rad51 activity, including a group of five proteins referred to as Rad51 paralogs (Rad51B, Rad51C, Rad51D, Xrcc2, Xrcc3). At the start of my work, cellular studies of human Rad51 (HsRad51) had shown only that it forms distinct nuclear foci in response to DNA damage. Additionally, no information regarding the cellular localization, potential ...