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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.
81

The Characterization of Endothelial-Mesenchymal-Transition in Response to TGF-beta and its Potential Role in Angiogenesis

Zours, Sonja Charlotte 13 September 2012 (has links)
Angiogenesis is the formation of new blood vessels by sprouting from pre-existing ones. Transforming growth factor-beta (TGFβ) promotes angiogenesis and is a known inducer of endothelial-mesenchymal transition (EndMT), a process whereby endothelial cells become fibroblastic and motile. We hypothesize that TGFβ-induced EndMT enables endothelial cells to detach from the mature vessel and migrate to form the sprout that becomes a new vessel during angiogenesis. This study characterized EndMT in response to TGFβ +/- vascular endothelial growth factor (VEGF). Bovine aortic endothelial cells (BAEC) were stimulated with TGFβ +/- VEGF for prolonged periods. Confocal imaging and immunoblotting analyses revealed the strongest EndMT response at 5 ng/ml of TGFβ after 144 hours of exposure. A three-dimensional collagen model of angiogenesis revealed a potential relationship between EndMT and blood vessel sprouting. These results suggest that EndMT induction in BAECs requires high concentrations and prolonged exposure to TGFβ and is not significantly influenced by VEGF. / NSERC
82

Investigating the dose-dependent signalling of Transforming Growth Factor-Beta in bovine aortic endothelial cells

Richard, Amy 03 October 2012 (has links)
Transforming growth factor-beta (TGFβ) is an important signaling molecule that regulates several cellular processes including angiogenesis. However, its effects on angiogenesis are complex, with it being pro-angiogenic only at low concentrations (Pepper et al., 1993). Evidence suggests that downstream signaling pathways of TGFβ may be activated in a dose-dependent fashion. In fact, previous work in our laboratory has shown that the non-canonical Par6 polarity pathway gets preferentially activated at low concentrations. Considering the different cellular effects of downstream signaling pathways, we propose that TGFβ may modulate its effects on angiogenesis via differential activation of the canonical Smad and non-canonical Akt, FAK, NFκB and Par6 polarity signaling pathways. Based on this premise, bovine aortic endothelial cells were treated with TGFβ1 and TGFβ2 at concentrations ranging from 0.05 to 5 ng/mL. The activation patterns of canonical and non-canonical signaling pathways were studied via western blotting; with the use of phospho-specific antibodies against Smad2, Akt, FAK and NFκB. Preliminary results reveal that high concentrations of both TGFβ1 and TGFβ2 (5 ng/mL) cause preferential activation of Smad2, while the Akt, FAK and NFκB signaling pathways do not appear to become activated in response to TGFβ1 or TGFβ2 at the concentrations and time points studied. These results suggest the effect of TGFβ on angiogenesis may not involve Akt, FAK or NFκB signaling, but may involve dose-dependent signaling of the Smad signaling pathway. / NSERC
83

Talin : a novel inducible antagonist of transforming growth factor-beta 1 (TGF-[beta]1) signal transduction

Rafiei, Shahrzad. January 2007 (has links)
The survival of breast cancer patients declines when tumors are invasive and have an increased possibility of metastasizing to distal sites. Transforming Growth Factor-beta (TGF-beta) suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells. However, at late stage of mammary carcinogenesis, due to genetic and epigenetic alterations, TGF-beta loses its cytostatic actions, and contributes to tumor invasion by promoting cell proliferation, Actin cytoskeletal reorganization, as well as Epithelial to Mesenchymal Transition (EMT). Despite the key role of TGF-beta1 in tumor suppression as well as tumor progression, the molecular mechanisms underlying the conversion of TGF-beta form an inhibitor of proliferation in mammary breast cancer cells to an inducer of their cell growth and EMT have not been fully elucidated. Thus, acquiring a basic knowledge on the mechanism of TGF-beta regulating its target genes and its contribution to cancer progression may highlight new avenues for cancer therapy development. This prompted us to further investigate and identify TGF-beta-inducible genes that may be involved in TGF-beta biological responses during tumorigenesis. / In this thesis, we identified Talin as a novel TGF-beta1 target gene that acts as an antagonist to inhibit TGF-beta-mediated cell growth arrest and transcriptional activity in mammary cancer cell line, MCF-7. Searching for new partners of activated Smads, we found that TGF-beta1 induces Talin translocation from cytosol to the plasma membrane where Talin physically interacts with the TGF-beta1 signaling components, the Smads and the receptors. Furthermore, we observed that TGF-beta1 stimulation leads to the formation of Actin stress fibers where Talin was detected at the end of these stress fibers. Taken all together, the obtained data show that TGF-beta1 positively induced expression of Talin and suggests a role for Talin, which acts as a negative feedback loop to control TGF-beta biological responses.
84

Mechanisms of action of transforming growth factor beta and activin in haematopoietic cells

Valderrama-Carvajal, Hector F. January 2007 (has links)
The aim of this work was to investigate the role of TGFbeta family members in the induction of cell growth arrest and apoptosis in immune cell types. The TGFbeta superfamily is a large group of evolutionary conserved polypeptide growth factors, involved in different physiological processes. Any deregulation of the different components of the TGFbeta signaling pathway, has been largely implicated in multiple human critical disorders including cancer. Activin, originally isolated from gonadal fluid, and more recently described as an antiproliferative and proapoptotic factor in different cell types has been implicated in different immune functions. In particular, activin and TGFbeta play an important role in the haematopoietic tissue. They are critical death inducers in the immune system contributing to the elimination of different activated immune cell types. Control of immune cell proliferation, activation and subsequent elimination of activated cell populations by cell growth arrest and apoptosis are critical events for controlling infections and preventing autoimmune disease. However, very limited information about the downstream target genes and their signaling mechanism that relay on the inhibitory effects on cell growth by activin and TGFbeta ligands. Using a screen for genes that are differentially regulated by activin and TGFbeta in haematopoietic cells, we found that the phospholipids phosphatase SHIP-1 was strongly upregulated by activin and TGFbeta. Thus, we hypothesized that TGFbeta and activin induce cell growth arrest in immune cells through up-regulation of SHIP-1 with a significant and subsequent decrease in PtdIns 3,4,5-P3 levels affecting cell survival. Furthermore, we attempted to characterize the different intracellular signalling pathways downstream of these serine/threonine kinase receptors that lead to SHIP-1 overexpression as well as the transcription factors involved in the mediation of transcriptional regulation of the SHIP-1 gene promoter. / Chapter 1 provides a broad introduction to the field of TGFbeta signaling focusing on TGFbeta-induced apoptosis in immune cell types and the biology of inositol phosphatases involved in phospholipide metabolism, mainly focused on SHIP-1. Chapter 2 contains data demonstrating that the activin/TGFbeta-induced cell growth arrests and apoptosis through expression of SHIP-1. Data in chapter 3 proved evidences about the cross-talk between the Smad and JNK MAP kinase signalling pathways and their role in the transcriptional regulation of the SHIP-1 gene promoter. Finally, chapter 4, is focused on the discussion and the propose model of how activin/TGFbeta-induced SHIP-1 expression blocks induction of cell survival signals. As a dynamic cellular and molecular process the induction of SHIP-1 by TGFbeta ligands might be in co-association with other apoptosis molecules leading to cell growth arrest and apoptosis in different cell populations of the immune system.
85

Role of non-Smad signaling pathways in transforming growth factor beta (TGFβ)-induced expression of chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes

Jahan, Naima 11 December 2013 (has links)
Chondroitin sulphate proteoglycans (CSPGs) from the glial scar inhibit axonal regeneration following spinal cord injury. CSPG expression can be induced by transforming growth factor β (TGFβ), which suggests that inhibition of TGFβ may reduce CSPG levels. Astrocytes were treated with cyclic AMP (cAMP), which reduced TGFβ signaling protein Smad2 in astrocytes. However, cAMP-treated astrocytes showed strong neurocan expression following TGFβ treatment, which suggests that TGFβ may mediate CSPG expression through non-Smad pathways. Smad2 or Smad4 were knocked down in astrocytes using siRNA and TGFβ-induced neurocan, brevican and aggrecan expression were still observed, indicating that Smad signaling is not required for CSPG expression. Administration of a PI3K/Akt inhibitor produced significant reductions in neurocan, brevican and aggrecan expression in astrocytes, which suggests that PI3K/Akt pathway mediates CSPG expression. Erk1/2 inhibitor treatment did not reduce CSPG expression significantly. Targeting non-Smad signaling pathways may therefore be effective strategies to reduce CSPG expression following injury.
86

Inhibition of cellular proliferation by retinoids and transforming growth factor-betas in bovine mammary cells correlates with increased connexin43 expression

Woodward, Terry L. January 1996 (has links)
Bovine fibroblasts and epithelial cells were isolated from surgically biopsied mammary tissue. Characterization of population doubling time, cytoskeletal intermediate filaments, cryopreservation survival, and viability were performed on all fibroblast and epithelial cells. Several clonal fibroblast cell lines were cotransfected with a plasmid bearing the SV-40 Large-T-antigen, and the pSV-2 neo plasmid. Transfected cells were subsequently selected with G418 sulfate and cloned. / MAC-T cells and non-clonal primary bovine mammary epithelial cells proliferated in response to IGF-I, insulin, serum and serum albumin. MAC-T cells did not proliferate when cultured in EGF, estrogen, progesterone, estrogen+progesterone, growth hormone, prolactin, and only modest proliferation was obtained after TGF-$ alpha$ treatment. Subsequent experiments used serum, insulin or IGF-I (and its analogues) to stimulate cellular proliferation. Serum albumin was not added to serum-free media preparations since it stimulated cellular proliferation. / TGF-$ beta$ receptors were characterized in MAC-T cells and normal fibroblasts. Affinity labelling studies revealed that MAC-T and MF-2 cells contained type I, II, and III autoregulatable receptors. Fibroblast proliferation, was inhibited 50% by TGF-$ beta$. TGF-$ beta$ inhibited MAC-T cellular proliferation at concentrations among the lowest ever reported, ED$ sb{ rm 50}$ = 4 pm. TGF-$ beta$ was not cytotoxic at concentrations 1000-fold higher. / Retinoic acid (RA) also inhibited proliferation of MAC-T cells. Inhibition of proliferation did not occur when cells were growth stimulated by IGF-I analogues that do not bind IGFBPs. Unlike TGF-$ beta$, RA treatment increased IGFBP-2 and decreased IGFBP-3 protein expression by cells into media and on the cell's membrane. RA was cytotoxic at concentrations 10-fold higher than ED$ sb{100}$. / Fibroblasts and epithelial cells expressed the gap junction (GJ) protein, connexin43, with transformed fibroblasts expressing significantly less connexin43. Perinuclear and cell surface connexin43 was immunodetected in epithelial and fibroblasts cells. TGF-$ beta$, RA or cAMP, increased connexin43 protein expression, especially phosphorylated species. Only cAMP noticeably altered immunolocalization patterns of connexin43, causing a shift from perinuclear pools to the cell surface. None of the growth inhibitors affected GJ communication as measured by dye transfer. Therefore, mammary epithelial cells are growth inhibited by TGF-$ beta$ and RA by distinct mechanisms and both growth inhibitors significantly enhance the gap junction protein, connexin43, without increasing GJ communication.
87

Characterization of Dante, a novel member of the DANCerberus family TGF-[beta] inhibitors

Popescu, Olivia January 2003 (has links)
TGFbeta signaling peptides have been shown to play increasingly diverse roles in metazoan development and tissue homeostasis. Negative regulation of TGFbeta ligands such as Nodal can be achieved by physical interactions with inhibitory molecules. Dante is a recently identified putative member of DAN/Cerberus family of TGFbeta inhibitors. Previously shown to be unilaterally expressed on the right side of the mouse node, Dante has been suggested to play a role in Left-Right axis formation possibly by inhibition of Nodal molecules. The aim of this study was to further characterize Dante and to determine whether it can physically interact with Nodal. First, a longer Dante cDNA was isolated in an attempt to clone the full-length transcript. Furthermore, Dante expression pattern was analyzed during murine development and adult tissues. Lastly, co-immunoprecipitation experiments demonstrated that Dante is able to physically interact with Nodal, providing further support for its potential role as a Nodal inhibitor.
88

Recovery of transforming growth factor-[beta]2 from Whey Growth Factor Extract with immunoaffinity techniques / by Benjamin Matthew Hunt.

Hunt, Benjamin Matthew January 2000 (has links)
Includes errata on last 3 leaves. / Includes bibliographical references (leaves 232-246). / xix, 246 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes attempts to develop an immunoaffinity process for commercial-scale purification of TGF-[beta]2 from Whey Growth Factor Extract / Thesis (Ph.D.)--Adelaide University, Dept. of Chemical Engineering, 2001
89

Recovery of transforming growth factor-[beta]2 from Whey Growth Factor Extract with immunoaffinity techniques / by Benjamin Matthew Hunt.

Hunt, Benjamin Matthew January 2000 (has links)
Includes errata on last 3 leaves. / Includes bibliographical references (leaves 232-246). / xix, 246 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes attempts to develop an immunoaffinity process for commercial-scale purification of TGF-[beta]2 from Whey Growth Factor Extract / Thesis (Ph.D.)--Adelaide University, Dept. of Chemical Engineering, 2001
90

Molecular interactions of latent transforming growth Factor-β binding Protein-2 (LTBP-2) with fibrillins and other extracellular matrix macromolecules [electronic resource]: LTBP-2 competes with LTBP-1 for binding to Fibrillin-1 suggesting that LTBP-2 may modulate latent TGF-β storage

Hirani, Rena M January 2006 (has links)
Elastic fibres, a major component of many connective tissues, are composed of an amorphous elastin core surrounded by fibrillin - containing microfibrils. The function of these microfibrils appears to require the co - ordinated interactions of fibrillins with a range of extracellular matrix ( ECM ) macromolecules including, latent transforming growth factor - β ( TGF - β ) binding proteins ( LTBPs ). LTBPs share a high degree of structural similarity to fibrillins, since they both contain unique 8 - cysteine motifs. Of the four members of the LTBP family, LTBPs - 1, - 3 and - 4 covalently bind to latent forms of TGF - β. LTBP - 1 has been shown to interact with the N - terminal domains of fibrillin - 1 and - 2 and LTBP - 4 interacts with the N - terminal domains of fibrillin - 1, suggesting that fibrillin - containing microfibrils may act as TGF - β stores and localise latent TGF - β complexes to the ECM. LTBP - 2 differs from other members of the LTBP family since it does not covalently bind latent TGF - β. However, LTBP - 2 strongly co - localises with fibrillin - containing microfibrils in a number of tissues suggesting that LTBP - 2 could have a structural role associated with these elements presumably independent of TGF - β storage, or could act to mediate specific microfibril - ECM interactions. To understand more about the function of LTBP - 2, this study involved screening for potentially important molecular interactions of LTBP - 2 with fibrillins and a variety of ECM proteins. Human recombinant LTBP - 2 ( r - LTBP - 2 ) was cloned, expressed and purified using a mammalian cell culture system. Solid phase binding assays were used to screen for interactions between r - LTBP - 2 and continguous fragments of fibrillin - 1 and - 2 as well as MAGPs, tropoelastin, collagens and proteoglycans. A cation dependant interaction was found between the C - terminal domains of LTBP - 2 and the N - terminal domains of fibrillin - 1, but not with the analogous region of fibrillin - 2. Thus, LTBP - 2 seems to have an exclusive role associated with fibrillin - 1 - containing microfibrils. Further studies found that the C - terminal region of LTBP - 2 competes with LTBP - 1 for binding to fibrillin - 1, suggesting that the binding site for LTBP - 2 on fibrillin - 1 is the same or in close proximity to that for LTBP - 1. Immunohistochemical analysis of LTBP - 1 and - 2 within developing human aorta indicated that both LTBPs co - localised with fibrillin - 1. However, the two LTBPs did have distinct distribution patterns in relation to each other, in that LTBP - 2 was found throughout the medial layer whereas LTBP - 1 was mainly located in patches of the outer medial layer. No regions of strong co - localisation of the two LTBPs were found. Thus, these findings suggest that LTBP - 2 could indirectly modulate the presence of TGF - β upon the fibrillin - containing microfibrils by competing for binding with the LTBP- 1 / TGF - β complex to these structures. Other binding studies showed a cation independent interaction between r - LTBP - 2 and an as yet unidentified component of a crude bovine collagen - IV extract. Since collagen - IV is a major component of basement membranes, an interaction between r - LTBP - 2 and a protein within this bovine collagen - IV preparation suggests LTBP - 2 may have a further function involving a basement membrane component. It will be interesting to determine if LTBP - 2 acts as a bridging molecule between basement membrane structures and fibrillin - containing microfibrils or if it has another function independent of these microfibrils. / Thesis (Ph.D.)--School of Medical Sciences, 2006.

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