Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 132-165.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 38-51).

L'hypervascularisation artérielle bronchique des dilatations des bronches contribue à l'afflux local de cellules inflammatoires et de protéines plasmatiques et favorise la survenue de saignements bronchiques. Les mécanismes de l'angiogénèse des vaisseaux bronchiques dans les dilatations des bronches sont peu connus, mais pourraient impliquer la voie du facteur de croissance endothélial (VEGF)-A.Nous avons émis l'hypothèse que l'infection bronchique dans les dilatations des bronches contribue à l'angiogénèse des vaisseaux bronchiques. Nous avons développé chez la souris un modèle d'infection bronchique persistante par l'instillation intratrachéale de billes d'agarose contenant du Pseudomonas aeruginosa. Nos résultats indiquent que l'infection bactérienne provoque l'angiogénèse des vaisseaux péribronchiques en 7 jours. P. aeruginosa induit la synthèse de VEGF-A par l'épithélium respiratoire in vitro et chez la souris par l'activation du récepteur de l'epidermal growth factor (EGF).Nous avons ensuite évalué l'effet de la perte de fonction de CFTR, l'anomalie caractéristique de la mucoviscidose (une cause génétique de dilatation des bronches), sur l'angiogénèse bronchique et l'expression de facteurs pro-angiogéniques. Ces études ont été menées à partir de poumons de patients mucoviscidosiques, chez des souris mutées pour le gène cftr et par inhibition de CFTR sur des cultures de cellules épithéliales.Nos données indiquent que l'infection bronchique contribue à l'angiogénèse péribronchique, qui nécessiterait une communication épithélium/endothélium. L'épithélium bronchique de la mucoviscidose est dans un état pro-angiogénique en l'absence d'infection. / Abnormal proliferation of bronchial arteries in subjects with bronchiectasis contributes to the recruitment of inflammatory cells and plasma protein within the airways, and promotes endobronchial bleeding. Mechanisms of bronchial angiogenesis in bronchiectasis are largely unknown, but could implicate the vascular endothelial growth factor (VEGF)-A pathway.We hypothesized that bronchial infection that occurs in bronchiectasis contributes to angiogenesis of bronchial blood vessels. We developed a mouse model of persistent bronchial infection by intratracheal instillation of agarose beads containing Pseudomonas aeruginosa. Our results indicate that bacterial infection promotes angiogenesis of peribronchial blood vessels within 7 days. Further, P. aeruginosa induces VEGF-A synthesis in airway epithelium in vitro and in mouse in vivo via activation of the epidermal growth factor (EGF) receptor.Next we examined the role of CFTR defect, associated with cystic fibrosis (CF, a genetic cause of bronchiectasis), on bronchial angiogenesis and expression angiogenic growth factors. These studies were conducted using lung tissues obtained in CF subjects, in various strains of mice mutated for the cftr gene, and by inhibition of CFTR function in cultured airway epithelial cells.Our data indicate that bronchial infection contributes to peribronchial angiogenesis, which probably necessitate interaction of epithelial and endothelial cells. Cystic fibrosis airway epithelium may exhibit a pro-angiogenic phenotype in the absence of infection.

<p>Collagen crosslinking with a polypropyleneimine octaamine dendrimers, via carbodiimide chemistry, was further exploited to demonstrate the ability of this technology for various tissue engineering strategies, including tissue engineered corneal equivalents (TECE) and blood-contacting biomaterials. In addition, modification with extracellular matrix components and other biomimetic molecules may enhance tissue-host interactions for greater <em>in vivo </em>compatibility.</p> <p>First, the efficacy of the dendrimer crosslinking technology was further validated with commercially available collagen-based materials, from bovine or human sources (Chapter 4: Paper 1), as determined via transmittance, water uptake, differential scanning calorimetry, collagenase stability and <em>in vitro </em>cell compatibility. Despite gel formation, the matrix integrity was compromised with collagen-based materials manufactured under acidic conditions and purified via freeze-drying.</p> <p>To continue the theme of dendrimer crosslinked collagen gels as TECE materials, growth factor incorporation was investigated with epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), as a method for improving device epithelialization and subsequent host integration. However, given the short half lives of these growth factors, an effective growth factor delivery system is necessary to protect growth factor bioactivity. As heparan sulphate proteoglycans sequester and release heparin-binding growth factors <em>in vivo</em>, the use of heparinized dendrimer crosslinked collagen (CHG) gels for HB-EGF delivery would provide prolonged, controlled delivery, while maintaining growth factor effectiveness (Chapter 5: Paper 2). HB-EGF release was prolonged and capable of inducing human cornea epithelial cell (HCEC) proliferation. Thus, HB-EGF delivery from CHG gels could aid in TECE device retention through enhanced device-host integration via epithelialization.</p> <p>Alternatively, tethering EGF or HB-EGF to dendrimer crosslinked collagen (CG) gels could also supply growth factor stimulation in a manner that maintains bioactivity, while stimulating growth factor receptors continually with minute concentrations (Chapter 6: Paper 3). Growth factor uptake and bioactivity was assessed with radiolabeled growth factor and through <em>in vitro </em>epithelial cell culture, respectively. Surface-modification of CG gels with growth factors demonstrated greater bioactivity, compared to growth factor bulk-modification of CG gels.</p> <p>Finally, dendrimer crosslinked collagen gels, with pre-activated heparin (PH gels) were investigated as a tissue engineered blood-contacting biomaterial (Chapter 7: Paper 4), as we hypothesized that biomaterial induced coagulation is not only influenced by an anticoagulant surface, but also by the underlying material and that improved blood-biomaterial interactions may be achieved by utilizing a natural polymer that emulates biomimetic properties. Pre-activation of heparin was utilized to increase heparin gel content, while antithrombotic properties were evaluated via antithrombin and fibrinogen adsorption and plasma recalcification times. PH gels had increased heparinization, but extensive crosslinking compromised antithrombin-heparin interactions, compared to CHG gels. CHG gels demonstrated improved antithrombotic properties and further evaluation of these gels for blood-contacting applications is warranted.</p> / Doctor of Philosophy (PhD)

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics / Doctoral / Doctor of Philosophy

We have previously demonstrated that Llgl1 loss results in a gain of mesenchymal phenotypes and a loss of apicobasal and planar polarity. We now demonstrate that these changes represent a fundamental shift in cellular phenotype. Llgl1 regulates the expression of multiple cell identity markers, including CD44, CD49f, and CD24, and the nuclear translocation of TAZ and Slug. Cells lacking Llgl1 form mammospheres, where survival and transplantability is dependent upon the Epidermal Growth Factor Receptor (EGFR). Additionally, Llgl1 loss allows cells to grow in soft-agar and maintain prolonged survival as orthotopic transplants in NOD-SCID mice. Lineage tracing and wound healing experiments demonstrate that mammosphere survival is due to enhanced EGF-dependent migration. The loss of Llgl1 drives EGFR mislocalization and an EGFR mislocalization point mutation (P667A) drives these same phenotypes, including activation of AKT and TAZ nuclear translocation. Together, these data indicate that the loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. / A member of the epidermal growth factor (EGF) family; transforming growth factor alpha (TGF-a) shares significant homology with EGF and binds to the EGF receptor (EGF-R). Like EGF TGF-a plays important roles in normal physiological processes; but, as its name signifies, it has potent transforming ability; often associated with autocrine stimulatory mechanisms. The purpose of this study is to investigate a possible role for TGF-a and its receptor in certam human oesophageal squamous cell carcinoma (SCC) cell lines - namely, WHCO-I, -3 and -5. The wellstudied A431 epidermoid. carcinoma cell line was used throughout for control purposes. (Abbreviation abstract) / Andrew Chakane 2018