Thesis (M. Sc.)--York University, 2002. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 74-82). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004 & res_dat=xri:pqdiss & rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation & rft_dat=xri:pqdiss:MQ71602.

Thesis (M.S.)--Mechanical Engineering, Georgia Institute of Technology, 2004. / Dr. David Ku, Committee Chair ; Dr. Raymond Vito, Committee Member ; Dr. Alexander Rachev, Committee Member. Includes bibliographical references (leaves 103-106).

Thesis (Ph.D.)--Brown University, 2008. / Vita. Advisor : L. Ben Freund. Includes bibliographical references (leaves 89-97).

Ovarian cancer is the most lethal gynecological cancer. This is mainly due to widespread peritoneal dissemination and malignant ascites, in which angiogenesis, the formation of new blood vessels, is critical to both ascites development and its metastasis. Loss of E-cadherin is a well-established marker that characterizes the progression of metastatic tumors, including ovarian cancer. The release of a soluble form of E-cadherin (sE-cad) has been frequently associated with a rapid reduction of functional E-cadherin at the cell surface. Importantly, sE-cad is significantly present in ascites from women with stage III/IV ovarian cancer when compared to women with benign ovarian cysts. However, despite the clinical significance, most studies have focused on its role in weakening cell-cell adhesion, whether sE-cad itself has any biological function is not fully understood. Here it is shown for the first time a potent angiogenic role for sE-cad released from ovarian carcinoma. Soluble form of E-cadherin promoted the migration, permeability, and tubulogenesis of endothelial cells. These activities were also observed with a sE-cad/Fc chimera, and targeted inhibition using E-cadherin blocking antibodies completely prevented the sE-cad mediated effects. In addition, it was further revealed that sE-cad could be released from ovarian cancer cells in form of exosomes, a form of extracellular vesicles that play an important role in distant intercellular communication. sE-cad-positive exosomes were able to stimulate the angiogenic phenotype in vitro and functional neovascularization in a Matrigel implant model in vivo. The use of E-cadherin blocking antibodies resulted in diminished angiogenesis, confirming that the effect was sE-cad-positive exosomes specific. In search of the underlying mechanism by which sE-cad-positive exosomes promoted angiogenesis in endothelial cells which lacked E-cadherin, sE-cad was found to heterodimerize with VE-cadherin. This effect was associated with constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt and its effector β-catenin, but not p120 catenin. Similarly, the angiogenic phenotype could be reversed by inhibition of VE-cadherin, PI3K/Akt and β-catenin. A mass spectrometric proteomic analysis of the isolated exosomes revealed distinct membrane-bound proteases, especially disintegrin and metalloproteinase 10 (ADAM10) and matrix metalloproteinase 25 (MMP25) commonly associated with ovarian cancer progression, are implicated in sE-cad production. Small interfering RNA-mediated down-regulation of ADAM10 and MMP25 significantly inhibited sE-cad production. Moreover, hepatocyte growth factor, a multifaceted cytokine which is frequently elevated in ovarian cancer ascites, was shown to increase the expression of ADAM10 and MMP25 concomitant with an elevated level of sE-cad. Together, these results uncover a novel angiogenic role of sE-cad and a new mechanism of the action of sE-cad in tumor progression. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Cell adhesion to a substrate or another cell plays an important role in the activities of the cell, such as cell growth, cell migration and cell signaling and communication with extracellular environment or other cells. The adhesion of the cell to the extracellular matrix also plays a vital role in life, as it involves in healing process of a wound and formation of the blood clot inside a vessel. The spread of cancer metastasis tumors inside the body is mostly dependent on the mechanisms of the cell adhesion. The current work is devoted to studying deformation and adhesion of the cell membrane mediated by receptors and ligands in order to enhance the existing models. In fact phospholipid molecules as the constructive units of the cell membrane grant sufficient in-plane continuity and fluidity to the cell membrane that it can be acceptably modeled as a continuum fluid medium. Therefore a two dimensional isotropic continuum fluid model is proposed in here for cell under implementation of membrane theory. In accordance to lack of sufficient study on direct effect of presence of receptors on membrane dilation, the developed model engages the intensity of presence of receptors with membrane deformation and adhesion. This influence is considered through introduction of spontaneous areal dilation. Another innovation is introduced regarding conception of receptor-ligand bonds formation such that a nonlinear constitutive relation is developed for binding force based on charge-induced dipole interaction, which is physically admissible. This relation becomes also enriched by considering one-to-one shielding phenomenon. Diffusion of the receptors is formulated along the membrane under the influence of receptor-receptor and receptor-ligand interactions. Then the presented models in this work are implemented to an axisymmetric configuration of a cell to study the deformation and adhesion of its membrane. Another target of this work is to clarify the impacts of variety of material, binding and diffusion constitutive factors on membrane deformation and adhesion and to declare a rational comparison among them. / Graduate / 0548 / 0346 / golestan@uvic.ca

published_or_final_version / abstract / toc / Surgery / Master / Master of Philosophy

No description available.

During development, Dictyostelium discoideum cells assume muticellularity via their collective aggregation. Cell-cell adhesion is required for morphogenesis, cell differentiation, cell sorting and gene expression during development. TgrC1 is a heterophilic cell adhesion molecule which is indispendable for complete development. TgrC1 can be considered as the most important cell adhesion molecule for D. discoideum development because deletion of the tgrC1 gene completely arrests development at the loose aggregate stage and inhibits fruiting body formation. In order to investigate the biological role of TgrC1 during development, I have chosen to identify and charactize the extracellular heterophilic partner and the cytoplasmic binding partner(s) of TgrC1. Using different biochemical approaches, we identified TgrB1 as the heterophilic binding partner of TgrC1 and demonstrated that their association is mediated through IPT/TIG domains in the extracellular region of both proteins. Both tgrB1 and tgrC1 share the same transcriptional promoter and their spatiotemporal expression pattern is identical during development. We also examined the assembly of TgrC1-TgrB1 complexes via the split green fluorescence protein complementation assay and the fluorescence resonance energy transfer approach. Whereas TgrC1 is capable of forming cis-homodimers spontaneously, cis-homodimerization of TgrB1 depends on its trans-interaction with TgrC1. A model of the assembly process has been proposed. To investigate signalling events initiated by the interaction between TgrB1 and TgrC1, pull-down assays were employed and led to the identification of myosin heavy chain kinase C as the cytoplamic partner of TgrC1. Mutational analysis showed that the basic residues in the short cytoplasmic domain of TgrC1 are critical to the binding with MHCK-C. Disruption of the interation between MHCK-C and TgrC1 results in an alteration of cell motility at the aggregation stage and aberrant cell sorting in slugs. These studies have highlighted the role of TgrB1-TgrC1 complexes in the regulation of morphogenesis during Dictyostelium development.

No description available.

No description available.