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GSBS Dissertations and Theses

2005

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Characterization Of The Interaction Between The Attachment And Fusion Glycoproteins Required For Paramyxovirus Fusion: A Dissertation, Vanessa R. Melanson Dec 2005

Characterization Of The Interaction Between The Attachment And Fusion Glycoproteins Required For Paramyxovirus Fusion: A Dissertation, Vanessa R. Melanson

GSBS Dissertations and Theses

The first step of viral infection requires the binding of the viral attachment protein to cell surface receptors. Following binding, viruses penetrate the cellular membrane to deliver their genome into the host cell. For enveloped viruses, which have a lipid bilayer that surrounds their nucleocapsids, entry into the host cell requires the fusion of viral and cellular membranes. This process is mediated by viral glycoproteins located on the surface of the virus. For many enveloped viruses, such as influenza, Ebola, and human immunodeficiency virus, the fusion protein is responsible for mediating both attachment to cellular receptors and membrane fusion.

However ...


The Role Of Tec Kinases In Cd4+ T Cell Activation: A Dissertation, Cheng-Rui Michael Li Oct 2005

The Role Of Tec Kinases In Cd4+ T Cell Activation: A Dissertation, Cheng-Rui Michael Li

GSBS Dissertations and Theses

The Tec family tyrosine kinases Itk, Tec and Rlk are expressed in T cells. Previous studies have established that these kinases are critical for TCR signaling, leading to the activation of PLCγ1. To further understand the functions of Tec kinases in T cell activation, we took three different approaches. First, we performed a thorough analysis of CD28-mediated signaling events and functional responses with purified naïve T cells from Itk-/- mice and a highly controlled stimulation system. Data from this set of studies definitively demonstrate that CD28 costimulation functions efficiently in naïve CD4+ T cells in the absence of Itk. Second ...


Regulation Of Life Span By Daf-16/Forkhead Transcription Factor In Caenorhabditis Elegans: A Dissertation, Seung Wook Oh Oct 2005

Regulation Of Life Span By Daf-16/Forkhead Transcription Factor In Caenorhabditis Elegans: A Dissertation, Seung Wook Oh

GSBS Dissertations and Theses

The insulin/IGF-1 signaling pathway plays a pivotal role in life span regulation in diverse organisms. In Caenorhabditis elegans, a PI 3-kinase signaling cascade downstream of DAF-2, an ortholog of the mammalian insulin and insulin-like growth factor-1 (IGF-1) receptor, negatively regulates DAF-16/forkhead transcription factor. DAF-16 then regulates a wide variety of genes involved in longevity, stress response, metabolism and development. DAF-16 also receives signals from other pathways regulating life span and development. However, the precise mechanism by which DAF-16 directs multiple functions is poorly understood.

First, in Chapter II, we demonstrate that JNK is a novel positive regulator of ...


Regulation Of Cell Growth And Differentiation Within The Context Of Nuclear Architecture By The Runx2 Transcription Factor: A Dissertation, Daniel W. Young Sep 2005

Regulation Of Cell Growth And Differentiation Within The Context Of Nuclear Architecture By The Runx2 Transcription Factor: A Dissertation, Daniel W. Young

GSBS Dissertations and Theses

The Runx family of transcription factors performs an essential role in animal development by controlling gene expression programs that mediate cell proliferation, growth and differentiation. The work described in this thesis is concerned with understanding mechanisms by which Runx proteins support this program of gene expression within the architectural context of the mammalian cell nucleus. Multiple aspects of nuclear architecture are influenced by Runx2 proteins including sequence-specific DNA binding at gene regulatory regions, organization of promoter chromatin structure, and higher-order compartmentalization of proteins in nuclear foci. This work provides evidence for several functional activities of Runx2 in relation to architectural ...


Cd4+ T Cell Responses: A Complex Network Of Activating And Tolerizing Signals As Revealed By Gene Expression Analysis: A Dissertation, David Spaulding Brown Sep 2005

Cd4+ T Cell Responses: A Complex Network Of Activating And Tolerizing Signals As Revealed By Gene Expression Analysis: A Dissertation, David Spaulding Brown

GSBS Dissertations and Theses

Immunologic self-tolerance is maintained by both central and peripheral mechanisms. Furthermore, regulation of mature lymphocyte responses is governed by inhibitory as well as stimulatory signals. TCR recognition of cognate peptide bound to MHC molecules provides the initial stimulus leading to T lymphocyte activation and determines the antigen specificity of any subsequent response. However, lymphocytes must discriminate between foreign and self antigens presented by self-MHC molecules to maintain self tolerance and avoid pathological autoimmunity. Consequently, TCR ligation alone is reported to result in abortive activation, T cell anergy, apoptosis, and tolerance. Under normal physiological conditions, costimulatory signals modify lymphocyte responsiveness to ...


The Identification Of Cooperating Mutations In Tal1-Mediated Leukemia In The Mouse: A Dissertation, Jennifer Ann Calvo Sep 2005

The Identification Of Cooperating Mutations In Tal1-Mediated Leukemia In The Mouse: A Dissertation, Jennifer Ann Calvo

GSBS Dissertations and Theses

A sequential series of mutational events is necessary for the development of leukemia. The misexpression of TAL1, a basic helix-loop-helix (bHLH) transcription factor, is the most common mutation in T cell acute lymphoblastic leukemia (T-ALL). Tal1 transgenic mice develop leukemia with a long latency and incomplete penetrance indicating additional mutations are necessary to develop disease. To investigate additional mutational events that potentially contribute to TAL1-expressing T-ALL patients, we sought to identify cooperating mutations in Tal1 transgenic mice. Clinical studies implicated the loss of the INK4a/ARF locus, which encodes two tumor suppressors, p16INK4a and p14ARF, in the majority ...


Biochemical Mechanism Of Rna Interference In Higher Organisms: A Dissertation, Dianne S. Schwarz Aug 2005

Biochemical Mechanism Of Rna Interference In Higher Organisms: A Dissertation, Dianne S. Schwarz

GSBS Dissertations and Theses

RNA interference (RNAi) is an evolutionarily conserved, sequence-specific gene silencing pathway found in eukaryotes, in which 21-nucleotide, small interfering RNAs (siRNAs) guide destruction of a corresponding target mRNA. RNAi is a natural mechanism for both genome surveillance and gene regulation. Moreover, siRNAs can be transfected into cultured mammalian cells, causing the sequence-specific ‘knock down’ of an mRNA. My work in the Zamore lab has centered around the Drosophilain vitro system and cultured mammalian cells to study the RNA interference (RNAi) pathway. small interfering RNAs (siRNAs) are incorporated into the RNA-induced silencing complex (RISC), which culminates in the cleavage of ...


A Biochemical Dissection Of The Rna Interference Pathway In Drosophila Melanogaster: A Dissertation, Benjamin Haley Aug 2005

A Biochemical Dissection Of The Rna Interference Pathway In Drosophila Melanogaster: A Dissertation, Benjamin Haley

GSBS Dissertations and Theses

In diverse eukaryotic organisms, double-stranded RNA (dsRNA) induces robust silencing of cellular RNA cognate to either strand of the input dsRNA; a phenomenon now known as RNA interference (RNAi). Within the RNAi pathway, small, 21 nucleotide (nt) duplexed RNA, dubbed small interfering RNAs (siRNAs), derived from the longer input dsRNA, guide the RNA induced silencing complex (RISC) to destroy its target RNA. Due to its ability to silence virtually any gene, whether endogenous or exogenous, in a variety of model organisms and systems, RNAi has become a valuable laboratory tool, and is even being heralded as a potential therapy for ...


Characterization Of Jnk Binding Proteins: A Dissertation, Jeffrey Scott Rogers Jul 2005

Characterization Of Jnk Binding Proteins: A Dissertation, Jeffrey Scott Rogers

GSBS Dissertations and Theses

The JNK signal transduction pathway mediates a broad, complex biological process in response to inflammatory cytokines and environmental stress. These responses include cell survival and apoptosis, proliferation, tumorigenesis and the immune response. The divergent cellular responses caused by the JNK signal transduction pathway are often regulated by spatial and cell type contexts, as well as the interaction with other cellular processes. The discovery of additional components of the JNK signal transduction pathway are critical to elucidate the stress response mechanisms in cells.

This thesis first discusses the cloning and characterization of two novel members of the JNK signal transduction pathway ...


Chemokine Induction By Dengue Virus Infection: Mechanisms And The Role Of Viral Proteins: A Dissertation, Carey L. Medin Jul 2005

Chemokine Induction By Dengue Virus Infection: Mechanisms And The Role Of Viral Proteins: A Dissertation, Carey L. Medin

GSBS Dissertations and Theses

The focus of this thesis is the role of dengue virus in the induction of chemokines. Dengue virus (DENV) occurs as four distinct serotypes, called DENV 1,2,3,and 4. Symptomatic DENV infection ranges from a self limited febrile illness, dengue fever (DF), to a more severe disease, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). DHF is characterized by increased capillary permeability resulting in decreased plasma volume, which may be accompanied by hemorrhagic manifestations. Many factors including T cell cross reactivity, viral burden, antibody dependent enhancement and induction of chemokines and cytokines have been reported in DHF and ...


Mechanisms Of Host-Range Function Of Vaccinia Virus K1l Gene: A Dissertation, Ritu Rakshit Bradley Jul 2005

Mechanisms Of Host-Range Function Of Vaccinia Virus K1l Gene: A Dissertation, Ritu Rakshit Bradley

GSBS Dissertations and Theses

The KIL gene of vaccinia virus encodes for a host range protein; in the absence of which, the virus is unable to grow in certain cell lines (RK-13 and some human cell lines). KIL function can be complemented in RK-13 cells by the cowpox host range gene product CP77 despite a lack of homology between the two proteins except for ankyrin repeats. We investigated the role of ankyrin repeats ofthe K1L gene in the host-range restriction of growth in RK-13 cells. The growth of a recombinant vaccinia virus, with the K1L gene mutated in the most conserved ankyrin repeat, was ...


Egr-2 And Pd-1 Are Required For Induction And Maintenance Of T Cell Anergy: A Dissertation, Kenneth D. Bishop Jul 2005

Egr-2 And Pd-1 Are Required For Induction And Maintenance Of T Cell Anergy: A Dissertation, Kenneth D. Bishop

GSBS Dissertations and Theses

The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness ...


Cross-Reactive Cd8 T Cell Responses And Heterologous Immunity During Acute Epstein-Barr Virus Infection: A Dissertation, Shalyn Catherine Clute Jul 2005

Cross-Reactive Cd8 T Cell Responses And Heterologous Immunity During Acute Epstein-Barr Virus Infection: A Dissertation, Shalyn Catherine Clute

GSBS Dissertations and Theses

A person is exposed to many pathogens throughout their lifetime, and with the resolution of each infection, there remains a pool of pathogen-specific immune cells that protect that person from re-infection with the same pathogen. However, there is a great deal of evidence to suggest that the pool of pathogen-specific memory cells can also participate in the immune response to future infections with unrelated pathogens. Many believe T cells to be cross-reactive in nature because of their interaction with self antigens during development in the thymus and their interaction with foreign antigens once in the periphery. There are many features ...


Functions Of The Cdc14-Family Phosphatase Clp1p In The Cell Cycle Regulation Of Schizosaccharomyces Pombe: A Dissertation, Susanne Trautmann May 2005

Functions Of The Cdc14-Family Phosphatase Clp1p In The Cell Cycle Regulation Of Schizosaccharomyces Pombe: A Dissertation, Susanne Trautmann

GSBS Dissertations and Theses

In order to generate healthy daughter cells, nuclear division and cytokinesis need to be coordinated. Premature division of the cytoplasm in the absence of chromosome segregation or nuclear proliferation without cytokinesis might lead to aneuploidy and cancer.

The cyclin dependent kinases, CDKs, are a main regulator of the cell cycle. Timely increase and decrease in their activity is required for cell cycle progression. To enter mitosis, mitotic CDK activity needs to rise. CDK activity stays elevated until chromosome segregation is completed and exit from mitosis requires decrease in CDK activity.

Observations in several experimental systems suggest that coordination of cytokinesis ...


Cytoplasmic Localization Of Hiv-1 Vif Is Necessary For Apobec3g Neutralization And Viral Replication: A Dissertation, Melissa Ann Farrow May 2005

Cytoplasmic Localization Of Hiv-1 Vif Is Necessary For Apobec3g Neutralization And Viral Replication: A Dissertation, Melissa Ann Farrow

GSBS Dissertations and Theses

The binding of HIV-1 Vif to the cellular cytidine deaminase Apobec3G and subsequent prevention of Apobec3G virion incorporation have recently been identified as critical steps for the successful completion of the HIV-1 viral life cycle. This interaction occurs in the cytoplasm where Vif complexes with Apobec3G and directs its degradation via the proteasome pathway or sequesters it away from the assembling virion, thereby preventing viral packaging of Apobec3G.

While many recent studies have focused on several aspects of Vif interaction with Apobec3G, the subcellular localization of Vif and Apobec3G during the viral life cycle have not been fully considered. Inhibition ...


The Epigenetic Silencing Of Pmp24 During The Progression Of Prostate Cancer From An Androgen-Dependent To Androgen-Independent State In The Lncap Cell Model: A Dissertation, Mengchu Wu Jan 2005

The Epigenetic Silencing Of Pmp24 During The Progression Of Prostate Cancer From An Androgen-Dependent To Androgen-Independent State In The Lncap Cell Model: A Dissertation, Mengchu Wu

GSBS Dissertations and Theses

One important objective of prostate cancer (PCa) research is to understand the molecular basis underlying the progression of these cancers from an androgen dependent to an androgen independent state. Hypermethylation of the promoter CpG islands is associated with the transcriptional silencing of specific gene sets in each tumor type and subtype. Transcriptional silencing of antitumor genes via CpG island hypermethylation could be a mechanism mediating PCa progression from an androgen-dependent to an androgen-independent state.

Hypermethylation associated gene silencing has been reported for a great number of genes in PCa with the exception of the genes that undergo methylation associated silencing ...


Analysis Of Polarity Signaling In Both Early Embryogenesis And Germline Development In C. Elegans: A Dissertation, Yanxia Bei Jan 2005

Analysis Of Polarity Signaling In Both Early Embryogenesis And Germline Development In C. Elegans: A Dissertation, Yanxia Bei

GSBS Dissertations and Theses

In a 4-cell C. elegans embryo the ventral blastomere EMS requires polarity signaling from its posterior sister cell, P2. This signaling event enables EMS to orient its division spindle along the anterior-posterior (A/P) axis and to specify the endoderm fate of its posterior daughter cell, E.

Wnt pathway components have been implicated in mediating P2/EMS signaling. However, no single mutants or various mutant combinations of the Wnt pathway components disrupt EMS polarity completely. Here we describe the identification of a pathway that is defined by two tyrosine kinase related proteins, SRC-1 and MES-1, which function in parallel with ...


The Role Of Itk In T Cell Development: A Dissertation, Julie Ann Lucas Jan 2005

The Role Of Itk In T Cell Development: A Dissertation, Julie Ann Lucas

GSBS Dissertations and Theses

Itk is a member of the Tec family of non-receptor tyrosine kinases. It is expressed in T cells, NK cells, and mast cells. The purpose of this study was to determine the role of Itk in T cell development. Previous work from our lab and others has demonstrated that Itk is involved in signaling downstream of the T cell receptor and initial analysis of Itk-deficient mice revealed that these mice had some defects in T cell development. There are two stages of T cell development, the pre-T cell stage and the CD4+ CD8+ double positive stage, at which signals downstream ...


Regulation And Function Of Stress-Activated Protein Kinase Signal Transduction Pathways: A Dissertation, Deborah Marie Brancho Jan 2005

Regulation And Function Of Stress-Activated Protein Kinase Signal Transduction Pathways: A Dissertation, Deborah Marie Brancho

GSBS Dissertations and Theses

The c-Jun NH2-terminal kinase (JNK) group and the p38 group of mitogen-activated protein kinases (MAPK) are stress-activated protein kinases that regulate cell proliferation, differentiation, development, and apoptosis. These protein kinases are involved in a signal transduction cascade that includes a MAP kinase (MAPK), a MAP kinase kinase (MAP2K), and a MAP kinase kinase kinase (MAP3K). MAPK are phosphorylated and activated by the MAP2K, which are phosphorylated and activated by various MAP3K.

The work presented in this dissertation focuses on understanding the regulation and function of the JNK and p38 MAPK pathways. Two different strategies were utilized. First, I ...