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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Investigation of the phosphatidylinositol 3-kinase pathway in B cells

Ma, Kewei 05 1900 (has links)
There is hardly a cellular process that is not regulated in some way by phosphoinositides, which makes biochemical and physiological studies of these lipids extremely important. PI 3-kinases are key regulators of phosphoinositide metabolism and have been shown to affect a large variety of cellular responses. The key products of PI 3-kinases that have functional activity in higher eukaryotic cells are PI(3,4,5)P₃ and PI(3,4)P₂. PI(3,4,5)P₃ is universally accepted as one of the most important second messengers in signal transduction. However, our knowledge of the functions of PI(3,4)P₂ as a lipid second messenger is much less precise. In this dissertation, work was undertaken to elucidate the regulation of PI(3,4,5)P₃ and PI(3,4)P₂ production and downstream signaling in B cells. Cells with membrane targeted exogenous SHIP were utilized to manipulate phosphoinositide levels. The relationship of PI(3,4,5)P₃ and PI(3,4)P₂ levels to downstream PKB phosphorylation and activation was studied. PI(3,4,5)P₃ and PI(3,4)P₂ levels were found to closely correlate with PKB phosphorylation levels at Thr308 and Ser473, respectively. In addition, PI(3,4)P₂ levels determine the PKB activity in the cytosol; while PI(3,4,5)P₃ levels determine PKB activity at the plasma membrane. Different doses and different forms of B cell receptor (BCR) agonists were used for stimulation. PI 3-kinase activation was studied carefully following stimulation with low doses of anti-BCR antibody and F(ab')₂ fragments. Low concentrations of F(ab')₂ fragments produced higher levels of PI(3,4,5)P₃ than did a high concentration of F(ab')₂ fragments. Downstream PKB signaling was studied in these models. Similar conclusions were drawn from both SHIP over-expressing BJAB cells and dose-dependent BCR stimulations. We speculated that phosphoinositides’ regulation of the kinetics of PKB phosphorylation at Ser473 and Thr308 might be mediated by additional proteins. Investigation of plasma membrane-associated PKB showed that it formed a protein complex of around 400KD, which we attempted to characterize further with respect to PKB phosphorylation and association with lipids. In conclusion, phosphoinositide production is intricately regulated in vivo to control downstream signaling. The levels of PI(3,4)P₂ and PI(3,4,5)P₃ have precise and profound effects on PKB and other molecules such as TAPP and Bam32. This study has contributed new insight into the PI 3-kinase signaling pathway from the aspect of phosphoinositide lipid function.

On interaction and efficiency : prematch investments with hidden characteristics

Bidner, Christopher 05 1900 (has links)
I develop three models that are designed to aid in the analysis of environments in which agents i) benefit from interacting with others, and ii) optimally choose their characteristics mindful of the fact that such choices will influence the quality of interaction that they can expect. Of central interest is the ways in which a concern for interaction affects the efficiency with which agents choose their characteristics. The first two models contrast with previous work in that each agents' relevant characteristics are both unobserved and endogenously determined. The first model provides an explanation for credentialism in the labour market, and demonstrates how a concern for interaction can lead to over-investment in the relevant characteristic. The second model is motivated by human capital development in the presence of peer effects, and demonstrates how a concern for interaction can exacerbate an inherent under-investment problem. The third model retains the feature of unobserved characteristics, and contrasts with previous work by embedding frictions in the process by which agents compete for partners. The model is set in a labour market and demonstrates that outcomes of interest (equilibrium matching patterns, income, inequality and welfare) are generally not monotonic in the level of frictions.

Exploring Notch signaling pathways for breast cancer treatment

Han, Jianxun Unknown Date
No description available.

Insulin signaling, mitochondrial DNA copy number regulation and aging in Caenorhabditis elegans

Hu, Xiaobin Unknown Date
No description available.

The role of Phosphoinositide 3-Kinase in the Regulation of Cardiac Morphology and Function

Guo, Danny Unknown Date
No description available.

Interleukin-11 dependent NFkB activation in cultured intestinal epithelial cells

Leung, Jeffrey Daniel Hawk-Ling 01 August 2008 (has links)
Interleukin-11 (IL-11) is a cytokine that promotes intestinal epithelial resistance to injury, however the mechanisms remain incompletely understood. Evidence from the Ropeleski Lab supports IL-11 dependent activation of the transcription factor Nuclear Factor кB (NFкB), without the degradation of the inhibitor кB (IкB), which deviates from the classical mechanism involving proteolytic processing of IкB. Also, IL-11 mediates the modulation of genes associated with healing, such as cyclooxygenase-2 (COX-2). It was hypothesized that IL-11 activates NFкB in intestinal epithelial cells by direct modulation of NFкB which, in a physiological setting, stimulates restitution during the healing response in the gut. Both cultured rat IEC-18 and human HIEC epithelial crypt cells were used as models to investigate whether the effect of IL-11 was species-specific. Activated NFкB is targeted to the nucleus therefore immunoblotting of nuclear extracts for expression of NFкB protein subunits including p65, activated p65 (phospho-p65Ser536), p50, and RelB, as well as by immunofluorescent detection of p65 were used. Inhibition of IL-11 signaling was carried out using various pharmacological inhibitors in order to determine their effect on p65 phosphorylation. Mechanically wounded cells were used as a model of gut injury and restitution where immunoblotting was used to examine IL-11 dependent effects on phospho-p65Ser536 and COX-2 expression. The binding of p65 to the кB binding site on DNA was detected with an ELISA-based system. IL-11 treatment was associated with the nuclear accumulation of phospho-p65ser536 in epithelial cell lines. Inhibition of PI3K/Akt signaling with LY294002 and AktiVIII suggested a partial reduction in phospho-p65Ser536 while inhibition of MEK1,2 signaling with U0126 indicated almost a complete abrogation of phospho-p65Ser536 accumulation in the nucleus. Inhibition of inhibitor of кB kinase-β (IKKβ) with SC-514 also revealed a strong attenuation of IL-11 induced phospho-p65Ser536. Inhibition of p90RSK1 with SL0101 was inconsistent but suggested a partial blockage of phospho-p65Ser536 whereas inhibition of Src kinase with PP2, did not affect phospho-p65Ser536 in IL-11 treated IEC-18 cells. There was no increased binding of p65 to the кB binding motif on DNA after IL-11 treatment. In mechanically wounded cells treated with IL-11, nuclear phospho-p65Ser536 was unaffected; however there was an evident potentiation of wound-induced COX-2 expression compared to untreated cells. In conclusion, IL-11 activates NFкB signaling in a non-classical manner through the phosphorylation of the p65 subunit. The predominant pathway appears to involve IKK and MEK signaling. Also, IL-11 modulates COX-2 expression in response to wounding in intestinal epithelial cells. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2008-07-31 10:12:18.794

RASA3, a Key Player in Dopamine D2S Receptor-mediated MAPK Signaling

Ma, Xun 10 February 2011 (has links)
The short form of dopamine D2 receptor (D2S) functions as a presynaptic autoreceptor on dopamine neurons and has an inhibitory effect on dopaminergic tone. D2-MAPKs pathway is involved in many physiological events like production of prolactin and tyrosine hydroxylase (TH) expression. However, the effect of D2S receptor signalling on MAPKs is cell type specific, and is not fully understood.A recent study in our lab has identified a Gαi-interacting ras-MAPK inhibitor RASA3. Here, we showed that RASA3 is the key effector in D2-induced inhibition of MAPK by knockdown of endogenous RASA3 in the GH4 cell using RASA3 siRNA. We have also transfected a dominant negative RASA3 to compete with the endogenous RASA3 for the binding site on Ras. Both RASA3-siRNA and dominant negative RASA3 blocked D2S-induced inhibition of MAPK activation, clearly implicating that RASA3 is a key effector in Gαi3-dependent D2S mediated MAPKs inhibition To determine whether RASA3’s inhibitory effect could be reconstituted in fibroblast cells, the effect of RASA3 on D2-mediated ERK1/2 activation in COS7 cells was tested. Our results show that both active Gαi2 (or Gαi3) and active RASA3 are required for optimal inhibition of ERK1/2 activation in fibroblast COS7 cells.

Function and regulation of Drosophila Epsin in notch signaling

Xie, Xuanhua 26 January 2012 (has links)
Epsin is an endocytic protein that binds Clathrin, the plasma membrane, Ubiquitin, and also a variety of other endocytic proteins through well-characterized motifs. Although Epsin is a general endocytic factor, genetic analysis in Drosophila and mice revealed that Epsin is essential specifically for internalization of ubiquitinated transmembrane ligands of the Notch receptor, a process required for Notch activation. How Epsin promotes ligand endocytosis and thus Notch signaling is unclear. Here, by generating Drosophila lines containing transgenes that express a variety of different Epsin deletion and substitution variants, I tested each of the five protein or lipid interaction modules of Epsin for a role in Notch activation by each of the two Drosophila ligands, Serrate and Delta. here are five main results of this work that impact present thinking about endocytic machinery/Epsin, Epsin/ligand, or ligand/receptor interactions at the plasma membrane. First, I discovered that deletion or mutation of both UIMs destroys Epsin’s function in Notch signaling and has a greater negative effect on Epsin’s ability to function than removal of any other module type. Second, only one of the two UIMs of Epsin is essential. Third, the lipid-binding function of the ENTH domain is required for maximal Epsin activity. Fourth, although the C-terminal Epsin modules that interact with Clathrin, the adapter protein complex AP-2, or endocytic accessory proteins are necessary collectively for Epsin activity, their functions are highly redundant. Finally, I detected no ligand-specific requirements for Epsin modules. Most unexpected was the finding that Epsin’s Clathrin binding motifs were dispensable. All of these observations are consistent with a model where Epsin’s essential function in ligand cells is to link ubiquitinated Notch ligands to Clathrin-coated vesicles through other Clathrin adapter proteins. / text

Grade inflation and the signaling value of grades

Pattison, Evangeleen 08 November 2012 (has links)
Grades are the fundamental currency of our educational system; they incentivize student performance and academic behavior, and signal quality of student academic achievement to parents, employers, postsecondary gatekeepers, and students themselves. Grade inflation compromises the value of grades and undermines their capacity to achieve the functions for which they are intended. I challenge the ‘increases in grade point average’ definition of grade inflation employed by critics and argue that grade inflation must be understood in terms of the signaling power of grades. Analyzing data from four nationally representative samples of high school students, I find that in the decades following 1972: (a) grades have risen at high schools and dropped at four-year colleges, in general, and selective four-year institutions, in particular; and (b) the signaling power of grades has attenuated little, if at all. I conclude that the concerns of critics who warn of rampant grade inflation are misplaced. Grades at secondary and postsecondary institutions are just as meaningful now as they were four decades ago. / text

Mechanistic Studies of Vertebrate Hedgehog Signaling

Tukachinsky, Hanna 14 March 2013 (has links)
Metazoans use Hedgehog signaling to direct many stages of embryonic development, and deregulation of this pathway is implicated in many types of cancer. I investigated several steps of Hedgehog pathway transduction that were poorly understood in mechanistic terms. The mature Hedgehog ligand is produced by a self-proteolysis reaction that covalently attaches a cholesterol molecule to the signaling half of the protein. I showed that the catalytic cysteine forms a disulfide bridge that is essential for the folding and function of the C-terminal tail of Hedgehog, and identified two protein disulfide isomerases that remodel this bridge to free the catalytic thiol group after folding is complete. Using pulse chase assays to follow Hedgehog processing, I demonstrated that the self-proteolysis reaction takes place in the endoplasmic reticulum, that the cleaved C-terminal tail of Hedgehog is degraded before moving to the Golgi, and that Hedgehog mutants defective in processing get degraded in their entirety by the same route. Lipidated Hedgehog ligand requires the transmembrane protein Dispatched for secretion. I devised a system to test Dispatched function in cultured cells, and showed that some inactive Dispatched mutants fail to bind Hedgehog, while others bind more tightly than the wild type protein. Scube2 was implicated as a Hedgehog pathway component in zebrafish genetic studies. I showed that Scube2 is a secreted protein that binds Hedgehog via its cholesterol adduct and solubilizes it in aqueous media. Dispatched and Scube2 bind Hedgehog on opposing faces, and they function synergistically to release it from the membrane. Vertebrate Hedgehog signaling relies on intraflagellar transport through an antenna-like organelle called the primary cilium. The Hedgehog receptor Patched and transducer protein Smoothened localize to primary cilia in a mutually exclusive pattern, depending on Hedgehog ligand presence. I showed that cytoplasmic components of the pathway Suppressor of Fused (SuFu, a pathway inhibitor) and Glioma-associated oncogene transcription factors (the Gli family, the effectors of the pathway) localize to primary cilia and accumulate there when Smoothened is activated. SuFu and Gli form a complex that dissociates when the pathway is turned on, and this dissociation depends on trafficking through the cilium.

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