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Baker, Tabari M. "Regulation of microRNAs targeting the angiogenic switch molecule Fibroblast Growth Factor Binding Protein 1 by retinoic acid receptor activation." Thesis, Georgetown University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3618988.
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This dissertation examines the role of retinoic acid receptor activation in the post-transcriptional regulation of a fibroblast growth factor binding protein. Previous work showed that all-trans retinoic acid (ATRA) reduces mRNA expression of the angiogenic switch molecule, Fibroblast Growth Factor Binding Protein 1 (FGFBP1 or FGF-BP), independent of an effect on transcription of the FGFBP1 mRNA. I hypothesized that a retinoid-induced microRNA was involved in FGFBP1 mRNA loss. MicroRNAs (miRs) are 19-22 nucleotide (nt) single stranded non-coding RNAs that post-transcriptionally repress mature mRNA function, thereby reducing expression of their target proteins. The current dogma suggests that miRs canonically bind to the 3' untranslated region (UTR) of mRNA through a 7-nt seed-matched site. However, recent data indicate that miRs may also bind the open reading frame (ORF) of mRNAs. In this dissertation, I show that miR-27b-3p and miR-125a-5p are induced by ATRA and target FGFBP1. Overexpression of miR-27b-3p and miR-125a-5p rapidly reduced FGFBP1 mRNA levels through a target site in the open reading frame of the FGFBP1 mRNA. Both microRNAs showed specificity for regions within the ORF of FGFBP1, suggesting that these microRNAs may also be involved in inhibiting translation of the FGFBP1 protein. Next generation sequencing data from The Cancer Genome Atlas shows that loss of these microRNAs is characteristic of several epithelial cancers, including head and neck, lung, and cervical squamous cell carcinomas, suggesting a tumor suppressor role for miRs 27a-3p and 125a-5p. In total, these data suggest an important regulatory role for miRs 27b-3p and 125a-5p in the oncogenesis of squamous cell carcinomas, through modulation of FGFBP1 expression.
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Yateman, Martin Edward. "Regulation of human fibroblast insulin-like growth factor (IGF)-binding proteins by IGF-1 and cytokines, mechanisms of action and effects upon IGF bioactivity." Thesis, Queen Mary, University of London, 1995. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1742.
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The insulin-like growth factors, IGF-I and IGF-II, are ubiquitous polypeptide molecules that have mitogenic and metabolic actions in a wide variety of cell types, and consequently play a major role in mammalian growth and development. Unlike many other peptide hormones, IGF levels and their bioactivity are highly dependent upon the secretion of a family of six specific binding proteins, named IGFBPs. In this thesis, we have developed a normal human fibroblast in vitro cell culture model to investigate both factors that affect IGFBP secretion, the mechanisms behind such regulation, and also the effect of IGFBP modulation upon subsequent IGF-I mitogenic activity. Firstly, we have examined the possible role that the recently discovered IGFBP proteases may have in determining the effect of IGF-I on IGFBP-3 abundance in fibroblast conditioned media. We show that IGF-I increased IGFBP-3 when assessed by ligand blotting, but did not increase immunoreactive IGFBP-3, a discrepancy that could be explained by further data showing an inhibitory effect of IGF-I on the activity of the fibroblast IGFBP-3 protease. Thus, IGF-I protection of IGFBP-3 from enzymatic degradation may help explain the post-transcriptional, non-receptor mediated 'stimulation' of IGFBP-3 by IGF-I in these cells. We also show for the first time the ability of a number of cytokines to regulate IGFBP secretion, perhaps indicating a novel pathway of communication between these immune cell molecules and the IGFs. The inflammatory cytokine interleukin 113(] L-16) inhibited Hs68 fibroblast IGFBP-3 secretion by down-regulating its gene expression, whilst tumour necrosis factor oc (TNF(x) had a similar inhibitory effect on IGFBP-3 and IGFBP-4 but acted via a post-transcriptional mechanism. The exact nature of the TNF(x effect remains to be determined as no evidence was found to suggest TNF(x increased IGFBP protease activity, or that TNF(x removed IGFBPs from the conditioned media by increasing the proportion immobilised on the cell surface. The inhibition of IGFBP secretion by TNF(x was observed to have marked effects upon the mitogenic activity of IGF-I in these cells, with a five-fold increase in sensitivity to the growth factor seen in a novel cytochemical bioassay. 1 Inhibition of fibroblast IGFBP secretion appeared to be restricted to certain cytokines as IL-6 had no effect, whilst high doses of interferon gamma abolished the TNF(X effect. Conversely, transforming growth factor 6 (TGFB) directly stimulated fibroblast IGFBP-3 secretion, via an increase in gene expression, and subsequently resulted in the reduction in the mitogenic activity of IGF-I. These data indicate that a variety of mechanisms can be employed by a number of factors to elicit changes in fibroblast IGFBP secretion, and that these changes may have direct consequencesin determining IGF-I bioactivity. Such is the importance given to the IGFs in maintaining normal somatic growth, changes in IGFBP secretion may contribute to the altered cellular growth and metabolism seen associated with cytokines in conditions as diverse as chronic infection, rheumatoid arthritis, cancer and the wound healing process.
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Gillies, Peter John. "Modulation of dermal microvascular endithelial cell responses to growth factors and haemostatic factors in the presence of vitronectin." Thesis, Queensland University of Technology, 2008. https://eprints.qut.edu.au/37176/1/Peter_Gillies_Thesis.pdf.
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In order to effect permanent closure in burns patients suffering from full thickness wounds, replacing their skin via split thickness autografting, is essential. Dermal substitutes in conjunction with widely meshed split thickness autografts (+/- cultured keratinocytes) reduce scarring at the donor and recipient sites of burns patients by reducing demand for autologous skin (both surface area and thickness), without compromising dermal delivery at the wound face. Tissue engineered products such as Integra consist of a dermal template which is rapidly remodelled to form a neodermis, at which time the temporary silicone outer layer is removed and replaced with autologous split thickness skin. Whilst provision of a thick tissue engineered dermis at full thickness burn sites reduces scarring, it is hampered by delays in vascularisation which results in clinical failure. The ultimate success of any skin graft product is dependent upon a number of basic factors including adherence, haemostasis and in the case of viable tissue grafts, success is ultimately dependent upon restoration of a normal blood supply, and hence this study. Ultimately, the goal of this research is to improve the therapeutic properties of tissue replacements, through impregnation with growth factors aimed at stimulating migration and proliferation of microvascular endothelial cells into the donor tissue post grafting. For the purpose of my masters, the aim was to evaluate the responsiveness of a dermal microvascular endothelial cell line to growth factors and haemostatic factors, in the presence of the glycoprotein vitronectin. Vitronectin formed the backbone for my hypothesis and research due to its association with both epithelial and, more specifically, endothelial migration and proliferation. Early work using a platform technology referred to as VitroGro (Tissue Therapies Ltd), which is comprised of vitronectin bound BP5/IGF-1, aided keratinocyte proliferation. I hypothesised that this result would translate to another epithelium - endothelium. VitroGro had no effect on endothelial proliferation or migration. Vitronectin increases the presence of Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) receptors, enhancing cell responsiveness to their respective ligands. So, although Human Microvascular Endothelial Cell line 1 (HMEC-1) VEGF receptor expression is generally low, it was hypothesised that exposure to vitronectin would up-regulate this receptor. HMEC-1 migration, but not proliferation, was enhanced by vitronectin bound VEGF, as well as vitronectin bound Epidermal Growth Factor (EGF), both of which could be used to stimulate microvascular endothelial cell migration for the purpose of transplantation. In addition to vitronectin's synergy with various growth factors, it has also been shown to play a role in haemostasis. Vitronectin binds thrombin-antithrombin III (TAT) to form a trimeric complex that takes on many of the attributes of vitronectin, such as heparin affinity, which results in its adherence to endothelium via heparan sulfate proteoglycans (HSP), followed by unaltered transcytosis through the endothelium, and ultimately its removal from the circulation. This has been documented as a mechanism designed to remove thrombin from the circulation. Equally, it could be argued that it is a mechanism for delivering vitronectin to the matrix. My results show that matrix-bound vitronectin dramatically alters the effect that conformationally altered antithrombin three (cATIII) has on proliferation of microvascular endothelial cells. cATIII stimulates HMEC-1 proliferation in the presence of matrix-bound vitronectin, as opposed to inhibiting proliferation in its absence. Binding vitronectin to tissues and organs prior to transplant, in the presence of cATIII, will have a profound effect on microvascular infiltration of the graft, by preventing occlusion of existing vessels whilst stimulating migration and proliferation of endothelium within the tissue.
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Montenegro, Luciana Ribeiro. "Estudo in vitro da sensibilidade ao IGF-1 de fibroblastos de crianças nascidas pequenas para a idade gestacional sem recuperação estatural pós-natal." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-08092009-132008/.
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Introdução: Crianças nascidas pequenas para a idade gestacional (PIG) apresentam maior risco de permanecerem com baixa estatura na vida adulta. Os fatores de crescimento insulino-símile tipo 1 e 2 (IGF-1 e IGF-2) são os principais fatores endócrinos determinantes do crescimento fetal. A maioria das ações conhecidas do IGF-1 e 2 é mediada via um receptor tirosina quinase, conhecido como IGF-1R. Recentemente, a insensibilidade ao IGF-1 foi identificada como uma das causas de retardo de crescimento em crianças nascidas PIG que não apresentaram recuperação espontânea do crescimento na vida pós-natal. Crianças afetadas apresentavam níveis elevados de IGF-1, IGFBP-3 além de microcefalia. O papel de defeitos pósreceptor na sinalização do IGF-1 como causa de retardo de crescimento pré e pós-natal ainda não foi investigado. Objetivo: Analisar in vitro a ação do IGF-1 em fibroblastos de crianças nascidas PIG. Material e métodos: Desenvolvemos cultura de fibroblastos de 2 controles (C1 e C2) e de 4 pacientes nascidos PIG (SGA1, SGA2, SGA3 e SGA4) com suspeita de insensibilidade ao IGF-1 por ausência de recuperação do crescimento na vida pós natal, resposta insatisfatória ao tratamento com hGH apesar de níveis normais/elevados de IGF-1. Foi confirmado do ponto de vista molecular que um dos pacientes (SGA1) apresenta Síndrome de Sílver- Russell com perda da metilação do alelo paterno da região ICR1 (imprinting center region 1) importante para a expressão do IGF-2. Defeitos no gene do IGF1 e IGF1R foram afastados por sequenciamento direto. As ações do IGF- 1 foram determinadas por ensaios de proliferação, análise da produção de IGFPB-3 em meio de cultura e estudos de fosforilação de proteínas da via de sinalização do IGF-1 em fibroblastos (AKT e ERK). Resultados: As linhagens SGA1, SGA2 e SGA3 proliferaram respectivamente 31%, 60% e 78% a menos sob estímulo de IGF-1 em relação ás linhagens controles. Já a linhagem SGA4 apresentou comportamento semelhante ás linhagens controles. No estudo da expressão do RNAm do IGF1R por PCR em tempo real, não foi observada diferença significativa na expressão do IGF1R nas diversas linhagens PIG em relação aos controles, assim como o conteúdo total da proteína IGF-1R. Em relação á ativação da via MAPK, todas as linhagens dos pacientes PIGs apresentaram menor fosforilação ERK1/2 basal e após estímulo com IGF-1, quando comparadas com as linhagens controles (p < 0.001) apesar do conteúdo total de ERK1/2 ser semelhante. Já em relação a ativação da via PI3K, as linhagens SGA1, SGA2, SGA3 e SGA4 não diferiram significantemente em relação aos fibroblastos controles quanto à ativação de AKT pelo IGF-1. O conteúdo total de AKT também foi semelhante em todas as linhagens estudadas. O estudo da expressão de IGFBP3 mostrou um aumento da expressão deste peptídeo na linhagem de fibroblastos do paciente SGA1 (14X). O conteúdo de IGFBP-3 intracelular não sofreu alteração, porém comprovamos que a linhagem SGA1 secretava 2x mais IGFBP-3 para o meio de cultura. Apesar de apresentarem estrutura, expressão e conteúdo de IGF1R normais, essas mesmas 3 linhagens celulares que apresentaram menor proliferação também apresentaram diminuição na fosforilação de ERK após tratamento com IGF-1. Mesmo sob o estímulo com desIGF-1 (um análogo do IGF-1 com baixa afinidade por IGFBPs mas que preserva sua capacidade de ativar o receptor IGF-1R) a ativação de ERK e a proliferação celular se manteve abaixo dos das linhagens controles. O estudo do conteúdo total de GRB10 foi semelhante em todas as linhagens celulares. Conclusão: Três dos 4 pacientes PIG estudados apresentaram insensibilidade pós-receptor ao IGF-1. A linhagem celular SGA1, obtida de um paciente com hipometilação do ICR1 11p15 causando SSR, demonstramos um aumento da expressão e secreção de IGFBP-3, o qual não se mostrou responsável por inibir a ação do IGF-1 nestes fibroblastos. Novos estudos devem ser desenvolvidos para identificar o defeito molecular responsável pela insensibilidade ao IGF-1 a nível pósreceptor observada nestes pacientes.Introduction: Children born small for gestational age (SGA) have a higher risk of staying with short stature in adulthood. The insulin-like growth factors (IGF-1 and IGF-2) are the main endocrine factor determining fetal growth. Most of the known actions of IGFs are mediated by IGF-1R, a tyrosine kinase receptor. Recently, the IGF-1 insensitivity was identified causing growth retardation in children born SGA who who did not present spontaneous catch-up growth in postnatal life. Affected children had elevated IGF-1 and IGFBP-3 levels in addition to microcephaly. The role of post receptor defects in IGF-1 signaling on the deficit of growth is still unclear. Objective: To assess IGF-1 action and signaling in vitro in fibroblasts from SGA children. Methods: Fibroblasts cell cultures were developed from 2 controls (C1 and C2) and 4 patients with pre- and post-natal growth retardation (SGA1, SGA2, SGA3 and SGA4). IGF-1 insensitivity was demonstrated by severe pre and postnatal growth impairment without any evident cause, IGF1 SDS > 0 and poor growth response during high doses of hGH treatment. Three SGA patients presented microcephaly. Defects in the gene of the IGF1 and IGF1R were excluded by direct sequencing. One patient (SGA1) presents the Silver- Russell syndrome (SRS) with loss of methylation of the paternal allele in the ICR1 (imprinting center region 1) chromosome 11p15, important for IGF-2 expression. IGF-1 action was assessed by cell proliferation by colorimetric assay. IGF-1 signaling was assessed by AKT and ERK phosphorylation after IGF-1 stimulation through SDS-PAGE of intracellular extract followed by immunoblotting with specific antibodies. The expression of IGF1R and IGFBP3 gene was determined by Real-time quantitative PCR and the levels of the IGF-1R and IGBP-3 protein by direct immunoblotting. Results: The SGA1, SGA2 and SGA3 cell lines proliferated 31%, 60% and 78% less under IGF-1 stimulation in comparison of controls fibroblasts, respectively. The expression of IGF1R mRNA and the level of total amount of IGF-1R protein were similar in all SGA and control cell lines. Despite normal IGF-1R structure and quantity, the same 3 SGA cell lines that presented low proliferation response also had 50 to 85% lower ERK phosphorylation after IGF-1 treatment (p <0.001), although the similar total content of ERK1/2. In relation to PI3K pathway activation, all SGA cell cultures presented normal AKT phosphorilation. Fibroblasts from the SGA1 patient presented a 14x increase in IGFBP3 mRNA and 2x more IGFBP-3 secretion to culture serum medium. Treatment with desIGF-1, an IGF-1 analogue with low affinity for IGFBPs although retains its ability to activate the IGF-1R, did not recover cell proliferation or ERK phosphorylation. All cell lines presented similar amount of GRB10 protein Conclusion: Three of 4 SGA patients showed evidence of post-receptor IGF-1 insensitivity. The cell line SGA1, obtained from a SRS patient with ICR1 hypomethylation, showed increased expression and secretion of IGFBP-3, which was not directly responsible for inhibition in IGF- 1 action. Further studies should be developed to identify the molecular cause of IGF-1 post-receptor insensitivity observed in our patients.
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Marshall, Nicholas John. "The influence of insulin-like growth factor 1 and its analogues on fibroblasts and dermal wound healing." Title page, table of contents and synopsis only, 1998. http://web4.library.adelaide.edu.au/theses/09MD/09mdm3685.pdf.
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Includes bibliography (leaves 191-219). Examines the levels of insulin-like growth factor and the presence of IGF binding proteins in human wound fluid. Tests the potency of IGF-1 and 2 analogues in in vitro models of fibroblast activity and their effect on healing in normal and diabetic rodent wounds. Shows that IGF-1, IGF-2 and their binding proteins are present in fluid from a partial thickness cutaneous wound; that the binding proteins negatively modulate the activity of insulin-like growth factors in vitro, but that the IGFs do not necessarily show enhanced activity in vivo at the wound site if binding protein affinity is decreased. Discusses possible roles of these binding proteins in wound repair.
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Martin, Christopher School of Biomedical Engineering UNSW. "Investigation of exogenous growth factors; platelet derived growth factor, insulin-like growth factor binding protein and fibroblast growth factor, and their influence on in vivo bone repair." Awarded by:University of New South Wales. School of Biomedical Engineering, 2006. http://handle.unsw.edu.au/1959.4/30405.
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This research investigated if exogenous growth factors (GFs), in particular platelet derived growth factor (PDGF), has an in vivo effect on the healing response of normal healthy bone. The research was orientated to study whether a clinical beneficial effect could be demonstrated. To achieve this two animal models were utilised, namely, a rabbit tibial osteotomy model and an ovine tibial defect and porous implant ingrowth model. The rabbit model comprised of a unilateral V-shaped tibial osteotomy, stabilised with an absorbable intramedullary pin and figure-of-eight tension band suture, with a 3 week survival period. The GFs tested in this model were 3 concentrations of PDGF, a single dose of insulin-like growth factor binding protein (IGF-BP) and a combination of the two. Each osteotomy was injected with a single bolus of collagen (control) or collagen containing GF (treatment) during surgery. After sacrifice tibiae were CT-scanned in situ, harvested and subject to 4-point bend testing. The callus, underlying bone and contralateral bone's greyscales and mechanical testing results were used for comparative analysis. The ovine model consisted of implanting 6 small rectangular shaped titanium alloy porous implants and one empty defect bilaterally in sheep's tibiae, for 4 and 6 weeks. The sheep were injected with tetracycline bone marker at 2 week intervals. The model's characteristics and any positional effects were initially investigated. Followed by an investigation into the influence of various exogenous GFs on the healing response and ingrowth characteristics of bone into the porous implants. The GFs investigated were PDGF, IGF-BP and fibroblast growth factor impregnated into the porous implants in a collagen carrier. Comparative analysis was done on results from 3-point bend testing of the bone/implant interface, image analysis to quantify percentage of bone, from scanning electron microscopy images of implant sections and confocal microscopy images of tibial defect sections. Analyses indicate that the GFs investigated have a direct and quantifiable positive in vivo effect. The more significant finding is that the growth factors have a potent systemic effect. These results were confirmed by both the sheep porous bone plug model and the rabbit tibial osteotomy model used within this research.
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Paripelly, Rammohan. "Molecular Level Interaction of Human Fibroblast Growth Factor-1 (hFGF-1) With Phloridzin." TopSCHOLAR®, 2013. http://digitalcommons.wku.edu/theses/1314.
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Fibroblast growth factors (FGFs) are a family of growth factors which includes twenty three proteins. FGFs work as modulators for various cellular activities like mitosis, differentiation and survival. Among the FGF family, human fibroblast growth factor-1 (hFGF-1), which is also known as acidic fibroblast growth factor, is a potent angiogenic agent, involved in the formation of new blood vessels in various tissues. hFGF-1 is regarded as a prototype of the FGF family. It serves as one of the potential targets in tumor inhibition and obesity due to its involvement in new blood vessel formation in cancerous regions and adipose tissues. In general, FGFs exert their action by binding to heparin, forming FGF-heparin complex, which can then bind to fibroblast growth factor receptors (FGFRs). Inhibition of FGF dependent signal transduction by heparin mimicking compounds has shown promising results in control and treatment of tumor growth. Naturally occurring glycoside called phloridzin found to have anticancer property. Phloridzin (2-glucoside of phloretin) has structural resemblance to heparin; it is a natural antioxidant, widely known for its antidiabetic activity, besides controlling tumor growth. Phloridzin can mimic heparin and compete with it for FGF binding. This binding can be agonistic or antagonistic in nature on FGF signal transduction. In the present study, we investigated the molecular level interaction between phloridzin and hFGF-1 using various biophysical techniques like steady state fluorescence, limited trypsin digestion and protein-NMR spectroscopy. hFGF-1 needed for the study was expressed in recombinant Escherichia coli cells. The expressed protein was then purified using heparin sepharose affinity chromatography. Both expression and purification were monitored using SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Conformational stability of purified hFGF-1 was assessed through steady state fluorescence. Purified hFGF-1 is in, its native, properly folded conformation. Interaction studies, such as thermal unfolding and limited trypsin digestion were performed to assess the thermal stability and solvent accessibility of hFGF-1 in the presence of phloridzin respectively. It was found from interaction studies that hFGF-1 in the presence of phloridzin shown increased thermal stability and increased resistance against trypsin digestion. In order to locate the sites of interaction on hFGF-1 surface, a protein-NMR study was performed. Exact sites of interaction of phloridzin on hFGF-1 surface were found. In future, isothermal titration calorimetry will be performed to determine kinetics of the enthalpy change and dissociation constant of phloridzin-hFGF-1 interaction. In vivo studies will also be performed after completion of in vitro studies, which will give an insight about possibility of phloridzin and hFGF-1 interaction under physiological condition
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Hamilton, Fairley. "Regulation of sex hormone binding globulin and insulin-like growth factor binding protein-1." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243549.
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Geitgey, Delaney Kate. "Evaluating the role of fibroblast activation protein and fibroblast growth factor 21 in growth hormone-induced adipose tissue fibrosis." Ohio University Honors Tutorial College / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1587596581428154.
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Öklü, Rahmi. "Expression of latent transforming growth factor-β1 binding protein-1 in atherosclerosis." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621723.
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Rajwani, Dr Adil. "Mechanisms by which Insulin-like Growth Factor Binding Protein-1 modulates Endothelial Function." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521475.
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Babajko, Sylvie. "Regulation transcriptionnelle de l'expression hepatique de l'insulin-like growth factor binding protein-1 (igfbp-1)." Paris 6, 1993. http://www.theses.fr/1993PA066505.
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Les insulin-like growth factor binding proteins (igfbps) modulent la biodisponibilite et les effets biologiques des igfs. Parmi les six igfbps identifiees a ce jour, igfbp-1 presente la distribution tissulaire la plus restreinte, puisqu'elle n'est exprimee que dans le foie et dans l'endometre. Nous avons etabli que les facteurs de transcription hnf1, v-hnf1 et dbp mais pas c/ebp participent a l'activation du promoteur proximal d'igfbp-1. Par ailleurs, une analyse simultanee, au cours du developpement, de l'activite transcriptionnelle du gene d'igfbp-1 dans le foie, des quantites d'arn correspondant et de proteine serique a permis de montrer un pic d'expression au cours de la periode perinatale essentiellement regule au niveau transcriptionnel. De plus, nous avons montre que l'insuline diminue l'expression d'igfbp-1 en inhibant partiellement l'activite du promoteur proximal et que l'ampc l'augmente grace a l'interaction adn-proteine se produisant au niveau du site potentiellement reconnu par creb. L'ensemble de nos resultats montre que la regulation transcriptionnelle de l'expression d'igfbp-1 est la resultante de nombreuses interactions entre le promoteur d'igfbp-1 et des facteurs de transcription ubiquitaires ou presentant une specificite tissulaire
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Wilson, Heather-Marie Porterfield. "The role of insulin-like growth factor binding protein-related protein-1 in human breast cancer /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/6352.
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Lindgren, Björn. "Regulation of insulin-like growth factor binding protein-1 (IGFBP-1) and implications in catabolic conditions /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2411-2/.
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Ni, Weimin. "The brain development retardation in insulin-like growth factor binding protein-1 transgenic mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq23442.pdf.
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Butler, Georgina Susan. "A novel approach to study interactions of insulin-like growth factor binding protein-1." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/35189.
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Insulin-like growth factor binding proteins (IGFBPs) are important modulators of IGF action. It is becoming clear that they play an important role in processes such as differentiation, growth and development. Although the six IGFBPs show a high degree of homology, little is known of their structure, interactions or functions. IGFBP1 is produced in large amounts by uterine decidua in human pregnancy. The aim of the project was to identify its ligand binding domain and to pinpoint residues which are responsible for specific binding of IGFs. This was attempted using phage display, a relatively new technique, which couples mutagenesis to functional screening. In principle, this allows desirable mutants to be selected from large pools. The method is especially suitable for studying IGFBP1, since existing knowledge of its structure is inadequate for any strategy involving directed mutations. Mammalian and bacterial expression systems were evaluated using wild-type IGFBP1, in preparation for production of mutants selected by phage display, with a view to testing structure-function relationships of IGFBP1 in vitro and in vivo to elucidate its role in pregnancy. Wild-type IGFBP1 was displayed on fd-phage and retained its IGF-binding properties. Several schemes were devised to select for IGFBP1 molecules with altered affinities for IGFI and/or IGFII, but these proved unsatisfactory for selection of IGFBP1 as IGF appears to be sequestered within the binding protein. Various random mutagenesis methods were unsuccessful, probably due to the high GC content of IGFBP1 cDNA. Hence, although the combination of random mutagenesis and phage display is a powerful technique for the screening and selection of large numbers of mutants, the technical difficulties could not be resolved in the time available.
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Vijayan, Aneesh. "A comparative study of insulin like growth factor binding protein-5 and transforming growth factor-beta 1 on epithelial-mesenchymal transition." Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502281.
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Fibrosis is a disease which is characterised by scarring of tissues due to excessive production of extracellular matrix molecules. It has been described as unresolved wound healing. Previous studies have implicated IGFBP-5 and TGF-β1 as pivotal players in fibrosis. This study was undertaken to compare the effects of IGFBP-5 and TGF-β1 , with respect to one particular aspect of the response injury, epithelial mesenchymal transition (EMT). 1 developed Epithelial and Mesenchymal clones from NMuMg (epithelial) cells which were characterised by morphology and by expession of cell-surface markers. The ability of the Epithelial clone to undergo EMT with TGF-β1 and its increased sensitivity to TGF-β1 treatment compared with their mesenchymal counterparts made it an effective model to examine the effects of IGFBP-5. lGFBP-5 was not able to drive an EMT process since it failed to decrease E-cadherin expression (a marker of epithelial cells) and downregulated fibronectin expression (a mesenchymal marker) in mesenchymal clones.
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Hills, Frank Adrian. "Levels of insulin-like growth factor-I (IGF-1) and IGF binding protein-1 in disorders of human fetal growth." Thesis, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417595.
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Foster, Ernest Byron Pascoe David D. "Acute regulation of IGF-1 by differential growth-factor-binding-protein expression, inhibition, and proteolysis." Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/SUMMER/Health_and_Human_Performance/Dissertation/Foster_Ernest_45.pdf.
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Boraie, Anwar Abdullah. "Insulin-like growth factor binding protein 1 (IGFBP-1) : a potential marker of insulin resistance and cardiovascular risk." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/843496/.
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Insulin resistance is a central feature of the metabolic syndrome and strongly associated with diabetes and cardiovascular disease. The frequently sampled intravenous glucose tolerance test (FSIVGTT) is an alternative method to the euglycaemic hyperinsulinaemic clamp technique for quantitation of insulin resistance. Other simple indices can also be derived from single time point fasting sample (e.g. homeostasis model assessment). The serum protein insulin-like growth factor binding protein 1 (IGFBP-1) is an emerging marker and may be useful in the assessment of insulin resistance. Few ethnic studies have been undertaken and to date, neither insulin resistance nor IGFBP-1 have been compared between Caucasian and Saudi population. The main aims of the project were therefore to directly compare insulin resistance between these two populations and to investigate IGFBP-1 as a marker of insulin resistance and cardiovascular risk. In addition the project aimed to investigate variations of different methods of insulin resistance over different time-intervals. After establishing the analytical criteria of an ELISA technique, serum IGFBP-1 was observed to be highly associated with the insulin sensitivity (Si) parameter derived from FSIVGTT (r = 0.79, p < 0.0001) in normal subjects (n = 22) and could therefore be used as a reliable marker of insulin resistance in these subjects. Total variation (reproducibility) was determined for serum IGFBP-1 in subjects with normal glucose tolerance (NGT = 15), impaired fasting glucose (IFG = 9), impaired glucose tolerance (IGT = 9) and type 2 diabetics (DM = 9). Reproducibility was 20.9%, 29.5%, 33.1% and 48.0% for subjects with NGT, IFG, IGT and DM respectively. IGFBP-1 measurement was least variable in NGT individuals and variability increased with deteriorating glucose tolerance. Insulin resistance was compared in subjects from two populations (33 Saudis and 28 Caucasians matched for adiposity) using FSIVGTT and several simple surrogate indices of insulin resistance. These subjects were from different categories of glucose tolerance. Saudis in the NGT category had a significantly lower mean Si (p < 0.01) and fasting IGFBP-1 (p < 0.05) compared to Caucasians. The data suggest that Saudis with NGT are more insulin resistant than matched Caucasians. In addition to this the phosphorylation status of serum IGFBP-1 was investigated in individuals with (n = 36) and without (n = 39) cardiovascular disease. Significant differences were found between the two groups in less-phosphorylated IGFBP-1 (p < 0.001), phosphorylated IGFBP-1 (p < 0.01) and their ratio (p < 0.01). IGF-I was negatively associated with the ratio (r = - 0.45, p < 0.0001). It therefore appears that low serum levels of different forms of IGFBP-1 could be used as a potential marker of coronary risk, and the ratio may be an index of biologically active IGF-I.
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Noble, Anthony M. "In vitro examination of vitronectin, insulin-like growth factor, insulin-like growth factor binding protein complexes as treatments to accelerate the healing of diabetic ulcers." Thesis, Queensland University of Technology, 2008. https://eprints.qut.edu.au/16670/1/Anthony_Michael_Noble_Thesis.pdf.
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It has previously been shown that VN can form complexes with IGF-II or IGF-I in combination with its binding proteins IGFBP-3 or -5. This study aimed to determine the efficacy of using these complexes as a treatment designed to accelerate wound healing, particularly in diabetic ulcers. The primary functions of skin cells in wound healing are attachment, proliferation and migration, thus these functions were assessed in response to these complexes in skin cells derived from patients with diabetic ulcers and from non-diabetic patients. These studies examined responses to the complexes in both skin keratinocyte and fibroblast cells. Furthermore, in order to investigate the mechanisms that underlie the responses observed, I also examined the ability of skin cells to retain these functional responses when the complexes incorporated an IGF-I analogue that does not activate the IGF receptor or when the cells had been pre-incubated with an anti-αv-integrin function blocking antibody. In addition, the ability of the cells to survive and grow when treated with the complexes under conditions mimicking the diabetic wound was assessed using growth assays in which the media contained elevated concentrations of glucose and calcium. I found that cells derived from skin from normal patients showed enhanced proliferation in response to these complexes, whereas only the presence of IGF-I and IGFBP seemed to be important in stimulating the proliferation of cells derived from diabetic patients. I also found that enhanced migration was observed in fibroblasts from diabetic ulcers in response to the complexes but these responses only required the presence of VN in normal cells. Both normal and diabetic keratinocytes showed enhanced migration in response to the complexes and the responses involved the interaction of both IGF-I and VN with their respective cell surface receptors. However the enhanced migration observed in diabetic ulcer derived keratinocytes was approximately half the level seen in normal keratinocytes. Furthermore, I showed that cells derived from skin from normal patients exhibited greater proliferation when treated with complexes in the presence of high concentrations of glucose and calcium ion compared to cells that were not treated with the complexes. Likewise, cells derived from skin surrounding diabetic ulcers were able to grow in media containing high levels of glucose and calcium when treated with VN:IGFBP:IGF-I complexes. In particular diabetic skin derived fibroblasts grown in high calcium media demonstrated enhanced proliferation when treated with the complexes, whereas diabetic keratinocyte cells seemed less affected by these conditions than their normal counterparts were. The findings in this thesis show that VN:IGFBP:IGF-I complexes can elicit enhanced growth and migration in cells derived from skin from both normal and diabetic patients. Further, these responses are maintained in conditions found in the diabetic wound microenvironment, namely in the presence of high glucose and high calcium. Together these findings demonstrate the potential of the VN:IGFBP:IGF complexes as wound healing agents to treat wounds, especially diabetic ulcers. Such delayed healing wounds represent a significant burden to health care systems and are one of the primary conditions that leads to the amputation of limbs. Current treatments do not address the co-ordination of ECM and growth factor action on cells that is here demonstrated to stimulate multiple wound healing related functional effects in skin cells. The data presented here represents important new information that may guide the design of new integrated therapeutics that may enhance the healing of recalcitrant diabetic ulcers.
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Nanayakkara, Sachith N. "The role of IGF-1 and hormone binding proteins in understanding insulin-associated equine laminitis." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/118300/1/Sachith_Nanayakkara_Thesis.pdf.
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Laminitis is a common and extremely painful hoof disease in horses. We know that it is caused by abnormally high levels of insulin, but the mechanism of insulin action is not known. One theory is that insulin over-stimulates the receptors for a related hormone, insulin-like growth factor-1, and that this leads to uncontrolled cell proliferation in the hoof, which ultimately causes the disease. The first part of the thesis examines this theory, by determining if insulin can activate IGF-1 receptors directly, or displace IGF-1 from its binding proteins in blood, thereby increasing the activity of IGF-1. Because some horses appear to be naturally resistant to developing insulin-induced laminitis, the second part of the thesis examines if these horses carry proteins in their blood that can bind to insulin and reduce its activity.
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Marsh, Andrew. "Characterisation of the type I IGF receptor binding surfaces of insulin-like growth factor 1 using protein engineering." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245705.
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Batra, Sumit. "Innovative Purification Protocol for Heparin Binding Proteins: Relevance in Biopharmaceutical and Biomedical Applications." TopSCHOLAR®, 2011. http://digitalcommons.wku.edu/theses/1062.
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Heparin binding (HB) proteins mediates a wide range of important cellular processes, which makes this class of proteins biopharmaceutically important. Engineering HB proteins could bring many advantages, but it necessitates cost effective and efficient purification methodologies compared to the currently available methods. One of the most important classes of heparin binding protein is the fibroblast growth factors (FGFs) and its receptors (FGFRs). In this study, we report an efficient off-column purification of FGF-1 from soluble fractions and purification of the D2 domain of FGFR from insoluble inclusion bodies, using a weak amberlite cation (IRC) exchanger. This approach is an alternative to conventional affinity column chromatography, which exhibit several disadvantages, including time-consuming experimental procedures and regeneration and results in high cost for production of recombinant proteins. Authenticity of the purified proteins was verified by SDS-PAGE and MALDI mass spectrum analysis. Results of the heparin binding chromatography and steady state fluorescence experiments showed that the FGF-1 and the D2 are in a native biologically active conformation. The findings of this study will not only aid an in-depth investigation of this class of proteins but will also provide avenues for inexpensive and efficient purification of other important biological macromolecules.
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Dunaiski, Vera. "Effects of IGF-1 or LR3IGF-1 infusion on components of the GH/IGF-1 axis in pigs /." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phd897.pdf.
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Harrela, Maija. "Twin and epidemiological studies on insulin-like growth factor binding protein-1 : relationships to insulin sensitivity and cardiovascular risk." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/harrela/.
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Aziz, Amir. "Enhancing vascular endothelial repair in the setting of insulin resistance : effects of insulin-like growth factor binding protein-1." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/8010/.
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Insulin resistance (IR) leads to the development of type 2 diabetes mellitus and predisposes to cardiovascular disease (CVD) through its link with endothelial dysfunction. Cardiovascular risk factors and iatrogenic damage lead to biochemical and structural injury to the endothelium. Endogenous repair mechanisms are in place to regenerate injured endothelium. Insulin resistance has recently been shown to impair endothelial repair. The endogenously produced circulating insulin-like growth factor binding protein-1 (IGFBP-1) is potentially protective in the vasculature by stimulating nitric oxide production and enhancing insulin signalling in the endothelium. Cross-sectional studies have shown an association between low IGFBP-1 levels and CVD. This raises the possibility of exploiting IGFBP-1 therapeutically to prevent CVD in patients with diabetes. This project investigated whether IGFBP-1 enhances vascular endothelial repair in insulin resistant mice in vivo and probed potential molecular mechanisms by examining the effects of IGFBP-1 on human endothelial cells (EC) and angiogenic progenitor cells (APCs) in vitro. Endothelial regeneration was enhanced following arterial endothelium-denuding injury in IRKO mice by over-expressing human IGFBP-1. This was not explained by altered abundance or function of APCs. Incubation with IGFBP-1 significantly enhanced the ability of human EC to adhere to and regenerate denuded human vein ex vivo. In EC, IR was mimicked by the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) which significantly inhibited EC migration and proliferation in vitro. Co-incubation with IGFBP-1 restored the migratory and proliferative capacity of EC. IGFBP-1 significantly increased FAK phosphorylation, induced rapid activation of RhoA, and increased expression of α5β1 and αVβ3 integrins in EC. These multifactorial effects of IGFBP-1 on EC responses and acceleration of endothelial regeneration in mice raise the possibility that manipulating IGFBP-1 could be a strategy to enhance endothelial repair in humans with IR.
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Hack, Nicole L. "The Insulin-Like Growth Factor-1 (IGF1) System as a Potential Biomarker for Nutritional Status and Growth Rate in Pacific Rockfish (SEBASTES SPP.)." DigitalCommons@CalPoly, 2017. https://digitalcommons.calpoly.edu/theses/1824.
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Growth performance in vertebrates is regulated by environmental factors including the quality and quantity of food, which influences growth via endocrine pathways such as the growth hormone (GH) / insulin-like growth factor somatotropic axis. In several teleost fishes, circulating concentrations of insulin-like growth factor-1 (Igf1) correlate positively with growth rate, and it has been proposed that plasma Igf1 levels may serve as an indicator of growth variation for fisheries and aquaculture applications. Here, I tested whether plasma Igf1 concentrations might serve as an indicator of somatic growth in olive rockfish (Sebastes serranoides), one species among dozens of rockfishes important to commercial and recreational fisheries in the Northern Pacific Ocean. I reared juvenile olive rockfish under food ration treatments of 1% or 4% wet mass per d for 98 d to experimentally generate variation in growth. Juvenile rockfish in the 4% ration grew 60% more quickly in mass and 22% faster in length than fish in 1% ration. Plasma Igf1 levels were elevated in rockfish under the 4% ration, and individual Igf1 levels correlated positively with growth rate, as well as with individual variation in hepatic igf1 mRNA levels. These data in olive rockfish support the possible use of plasma Igf1 as a positive indicator of growth rate variation in rockfishes. Using my findings from this experiment, I further investigated the use of this biomarker in wild rockfish by examining patterns of Igf1 variation in blue rockfish (Sebastes mystinus) caught within and outside of two Marine Protected Areas (MPAs) along California’s coast: Piedras Blancas MPA and Point Buchon MPA. Individual Igf1 levels correlated positively with increasing size as seen in laboratory reared fish. After correcting plasma Igf1 values for body size, circulating Igf1 was observed to be higher in blue rockfish within the boundaries of the Piedras Blancas MPA compared to fish from an adjacent site with no fishing restrictions. Igf1 levels in blue rockfish caught within the Point Buchon MPA, however, were similar to those outside of that MPA. These results suggest that blue rockfish within the Piedras Blancas MPA may experience enhanced growth relative to conspecifics outside of that MPA’s boundaries, and that such growth increases may be specific to MPA locations. My findings support previous studies that Igf1 is a positive indicator for growth in teleost fish and can be used as a tractable biomarker in wild rockfish which could enhance management efforts of fish stocks within marine protected areas.
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Kachra, Zarin. "Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) mRNA levels in cultured rat hepatocytes." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41300.
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The liver is a major site of production of circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs). We have used primary cultured rat hepatocytes maintained under serum free conditions to explore the regulatory role of various hormones on hepatic IGF-I and IGFBP-1 mRNA levels.IGF-I mRNA levels were stimulated 2.0 to 2.5 fold by bovine growth hormone (bGH) and 1.8 to 2.0 fold by glucagon but on combining bGH and glucagon, a synergistic effect was observed and IGF-I mRNA level was augmented 10 to 12 fold. Octreotide blocked the hGH induced stimulation of IGF-I production in serum and hepatic IGF-I mRNA levels in hypophysectomized rats. This effect could have been partly due to the low levels of glucagon in serum when hypophysectomized rats were treated with hGH and octreotide. Octreotide was also found to inhibit GH stimulated IGF-I mRNA levels in rat hepatocytes.
The unique synergy observed with glucagon and bGH on IGF-I mRNA levels in hepatocytes was not reproduced by T$ sb3$, oPRL, dexamethasone, EGF or insulin when each was added in combination with bGH or glucagon. Like glucagon, the addition of IBMX or (Bu)$ sb2$cAMP stimulated IGF-I mRNA levels 1.8 to 2.0 fold, but in the presence of bGH, IGF-I mRNA levels were stimulated 10 to 12 fold. PMA stimulated IGF-I mRNA levels 1.2 to 1.4 fold but displayed no synergism when added with bGH. The stimulatory effect of bGH plus glucagon on IGF-I mRNA levels was inhibited in PKC depleted cells, in the presence of inhibitors of PKC and in the presence of cycloheximide. bGH had no posttranscriptional effect on IGF-I mRNA stability whereas glucagon or (Bu)$ sb2$cAMP stabilized IGF-I mRNA at a posttranscriptional level.
In summary, the major hormonal regulators of hepatic IGF-I mRNA levels appear to be GH and glucagon. Hepatic IGF-I mRNA levels are regulated by pathways involving protein kinase C and, protein kinase A as well as by synthesis of one or more protein(s).
Glucagon and dexamethasone each stimulated IGFBP-1 mRNA levels 3 to 4 fold whereas bGH and T$ sb3$ each inhibited IGFBP-1 mRNA levels 45 to 70%. Insulin, which inhibited IGFBP-1 mRNA levels 95%, was the most powerful inhibitor and was also found to inhibit IGFBP-1 mRNA levels in the presence of dexamethasone. IBMX and (Bu)$ sb2$cAMP stimulated IGFBP-1 mRNA levels 6 to 8 fold whereas PMA inhibited IGFBP-1 mRNA levels 40 to 50%. The inhibitory effect of bGH on IGFBP-1 mRNA levels was abolished in PKC depleted cells and also in the presence of inhibitors of PKC. In the presence of cycloheximide, IGFBP-1 mRNA was superinduced by bGH. bGH had no posttranscriptional effect on IGFBP-1 mRNA whereas glucagon and (Bu)$ sb2$cAMP stabilized IGFBP-1 mRNA at a postranscriptional level.
In summary, bGH, T$ sb3$ and insulin inhibited whereas dexamethasone and glucagon stimulated IGFBP-1 mRNA levels in hepatocytes. Effect of glucagon may be via elevation of cAMP levels, whereas the effect of bGH may be via activation of PKC levels. The inhibitory effect of bGH appears to require synthesis of one or more protein(s) besides stimulation of PKC levels.
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Lemos, Nadiane Albuquerque. "Avaliação de IGF-1 (Insulin-like growth factor-1), IGFBP-1 e IGFBP-3 (Insulin-like to growth binding protein-1 e 3) no fluído folicular de pacientes infertéis com endometriose." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2002. http://hdl.handle.net/10183/2958.
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Tippana, Mangapathiraju. "Development of a novel tissue targeted nerve growth factor: Fibronectin chimeric protein as a potential therapeutic for peripheral nerve regeneration." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/120280/1/Mangapathiraju_Tippana_Thesis.pdf.
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This project sought to develop a novel regenerative fusion protein that directly targets nerve-tissue through the addition of a specific nerve-tissue binding domain. Combining select domains of the extracellular matrix protein fibronectin with nerve growth factor, a singular potent regenerative stimulant was developed. To better deliver the candidate therapeutic to nerve-tissue, a native tissue binding domain was added. This approach represents a novel approach to meet the challenges facing regenerative medicine, making use of growth factor: extracellular matrix interactions and tissue localisation to repair, regenerate and restore tissue function.
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Armbrust, Moritz [Verfasser]. "Der Zusammenhang zwischen den Blutplasmakonzentrationen des zirkulierenden Insulin-like-Growth-Factor-1 sowie des Insulin-like-Growth-Factor-Binding-Protein-3 und dem funktionell-neurologischen Outcome nach ischämischem Schlaganfall / Moritz Armbrust." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2016. http://d-nb.info/1100387617/34.
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Lubina, Solomon Alexandra. "The role of placental alkaline phosphatase in the regulation of insulin-like growth factor binding protein-1 in pregnancy complicated by diabetes." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-placental-alkaline-phosphatase-in-the-regulation-of-insulinlike-growth-factor-binding-protein1-in-pregnancy-complicated-by-diabetes(c906fb09-38d2-4f9b-a391-e24c7e9a539e).html.
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Introduction: Abnormal fetal growth remains a major problem in pregnancies complicated by diabetes and is associated with increased maternal and offspring mortality and morbidity. Insulin-like growth factors (IGFs) stimulate fetal growth while their effects are inhibited by binding proteins (IGFBPs). IGFBP-1 is a significant IGFBP in maternal and fetal circulation and the only binding protein acutely affected by glucoregulatory hormones; as such, IGFBP-1 is particularly important in pregnancy with diabetes. In plasma of healthy human adults, the fully phosphorylated (pIGFBP-1) isoform is predominant. During pregnancy the phosphorylation status of IGFBP-1 changes; in addition to pIGFBP-1, non-phosphorylated (np) IGFBP-1 and 3 lesser phosphorylated (lp) IGFBP-1 variants with lower affinity for IGF-I are detected in the maternal circulation. The change in the phosphorylation status of IGFBP-1 in pregnancy may provide a physiological mechanism for the increased IGF-I bioavailability at the maternal/fetal interface required for placental and fetal growth.Hypothesis: IGFBP-1 de-phosphorylation occurs at the maternal/fetal interface and this process is catalyzed by placental alkaline phosphatase (PLAP). Fetal overgrowth (macrosomia) in pregnancy with diabetes may be a consequence of elevated IGF-I action at the placenta secondary to increased PLAP activity.Methods and Results: In vitro: Explants of human term placentas from normal pregnancies (n=5), or their conditioned media (CM), were incubated with pIGFBP-1 in the presence or absence of an anti-PLAP function blocking antibody. Addition of pIGFBP-1 to explants resulted in its binding to the tissue and de-phosphorylation, with npIGFBP-1 isoforms appearing in the medium. pIGFBP-1 was not de-phosphorylated when cultures were carried out in the presence of anti-PLAP antibody. In solution phase assays, PLAP failed to de-phosphorylate pIGFBP-1. Thus, placenta de-phosphorylates IGFBP-1 as a result of PLAP activity, and this requires its binding to the tissue.To investigate factors which may affect the activity of PLAP, placental explants (n=3 for each series of experiments) were incubated with pIGFBP-1 in the presence of insulin, IGF-I/-II or under hyperglycemic or hypoxic conditions. Following incubation, the phosphorylation status of IGFBP-1 present in placental-CM was assessed by native electrophoresis and western blot. PLAP-mediated IGFBP-1 de-phosphorylation was not affected in vitro by hyperglycemia, hypoxia, insulin or IGF-I/-II. In vivo: 30 patients with any type of diabetes in pregnancy and 20 controls were recruited. Maternal/cord blood was collected at term and analysed for IGF-I/-II, total IGFBP-1 and the phosphorylation status of IGFBP-1. Placentas were analysed for PLAP expression and activity. The maternal blood levels of both IGFs and total IGFBP-1 were similar in the diabetes and control groups, while cord IGF-II was elevated in diabetes. Unexpectedly, the p/npIGFBP-1 ratio in maternal serum was elevated in patients with diabetes, which may be a result of decreased IGFBP-1 de-phosphorylation. In controls, maternal p/npIGFBP-1 ratio correlated with infant weight, whilst this correlation was not demonstrated in women with diabetes. Placental PLAP expression/ex-vivo activity and total IGFBP-1 levels in maternal serum were unaltered in diabetes and did not relate to fetal growth in either diabetes or control groups. Conclusions: The hypothesis that activated PLAP and therefore enhanced IGFBP-1 de-phosphorylation may increase the effect of IGF-I on placental cell turnover and accelerate fetal growth in diabetes was not supported by the results of this study. Further work is required to reveal mechanisms by which the maternal/placental/fetal IGF-IGFBP-PLAP pathways modulate fetal growth in normal and compromised pregnancy.
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Ekman, Bertil. "IGF-I in growth hormone deficiency and in type 1 diabetes /." Linköping : Univ, 2002. http://www.bibl.liu.se/liupubl/disp/disp2002/med757s.pdf.
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Berg, Ulrika. "The IGF-IGFBP system in aerobic exercise - with focus on skeletal muscle /." Stockholm : Institutionen för kvinnors och barns hälsa, Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-379-5/.
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Lacey, Derek. "NFκB independent pathway activation of rheumatoid arthritis FLS by macrophage migration inhibitory factor (MIF)." Monash University, Faculty of Medicine, 2003. http://arrow.monash.edu.au/hdl/1959.1/9457.
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Kurkinen-Räty, M. (Merja). "Preterm birth and preterm infant:a clinical study on certain etiological and diagnostic factors, and the outcome of infants." Doctoral thesis, Oulun yliopisto, 2000. http://urn.fi/urn:isbn:9514258266.
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Abstract
The aim of the present study was to evaluate whether bacterial vaginosis (BV) diagnosed in early pregnancy and
treated with vaginal clindamycin affects pregnancy outcome, and to investigate the predictive value of interleukins-6
(IL-6) and -8 (IL-8), and insulin-like growth factor-binding protein-1 (IGFBP-1) in cervical secretions, separately and
combined by cervical measurement with transvaginal ultrasonography, on preterm delivery. A further aim was to analyze
retrospectively the significance of absent or reversed end-diastolic velocity (AREDV) in the umbilical artery on
perinatal outcome, and to investigate the short- and long-term outcome of infants born prematurely as a result of various
causes (indicated preterm birth, preterm premature rupture of the membranes=PPROM).
Bacterial vaginosis (BV) was screened in 1956 women in a low-risk population at the first antenatal visit, using
Gram stain. One hundred and one of 143 BV-positive women were randomized to receive vaginal clindamycin or placebo.
Seventy-seven women at 22-32 gestational weeks with premature uterine contractions, and 78 controls were recruited for
assay of cervical IL-6, IL-8-, and IGFBP-1, and ultrasonographic measurements, which were repeated twice at two-week
intervals. Eighty-three women with AREDV in the umbilical artery in high-risk pregnancies at less than 34 gestational
weeks (e.g. pre-eclampsia, small-for-gestational age [SGA]) between the years 1988-95 were analyzed retrospectively as
regards perinatal outcome. Further, for 103 women between the 24th and the 33rd week of pregnancy, delivered by cesarean
section because of maternal or fetal indications, and for 103 matched women, between the years 1990-97, their infants
were analyzed as regards neonatal mortality and morbidity, and the outcome at one year of corrected age. Similarly, 78
women with PPROM at gestational weeks 17-30, and 78 controls were also analyzed.
The prevalence of BV was 7.3% (143/1956) and the preterm birth rate in women with BV was 9.9%. Preterm birth
occurred in 21% vs. 0% according to whether or not BV persisted. The preterm birth rate was 14% in the clindamycin group
vs. 6% in the placebo group. Cervical IL-6 at a concentration of 128 ng/L had a 73% sensitivity and 77% specificity in
predicting preterm birth (35% vs. 6%). The combination of IL-6 and a cervical index of > 0.2 increased the specificity to
97%, the sensitivity falling to 45%. Concentrations of IGFBP-1 were most elevated (> 21 μg/mL) in cases with
neonatal infections (36% vs. 2%). In cases of absent end-diastolic velocity (AEDV) the perinatal mortality (PNM) rate was
9%, compared with 36% in the reversed end-diastolic velocity (REDV) group. Respiratory distress (RDS) and hypoglycemia,
and chronic lung disease (CLD; 15% vs. 3%) occurred significantly more often in the indicated than in the spontaneously
preterm infants. The PPROM infants had more limb contractures (8% vs. 0%) and pulmonary hypoplasia (12% vs. 5%) and more
chronic lung problems up to one year of age than the spontaneously preterm born infants without PPROM.
The persistence of pregnancy BV is a risk factor for preterm birth, but vaginal clindamycin used in a low-risk
population in early pregnancy is of no use in reducing the preterm birth rate in cases of BV. The level of IL-6 has a
relatively low sensitivity and a limited role as a single method in clinical decision making but in combination with
cervical examination by ultrasonography it seems to have a predictive role in cases of threatened preterm birth. A
finding of AREDV in the umbilical artery is a warning signal of threatened fetal asphyxia. Infants born after indicated
preterm delivery (for fetal or maternal reasons) or PPROM are at risk of later chronic lung disease.
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Bayayibign, Biruhalem Assefa [Verfasser]. "Insulin-like growth factor (IGF) binding protein-2, independently of IGF-1, induces GLUT-4 translocation and glucose uptake in 3T3-L1 adipocytes / Biruhalem Assefa Bayayibign." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1172074402/34.
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Kekki, Minnamaija. "Prediction and prevention of spontaneus preterm delivery and peripartum infections by screening for cervical insulin-like growth factor-binding protein-1 and bacterial vaginosis in pregnancy." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/kekki/.
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Lubik, Amy Anne. "The role of insulin and IGF2 signalling on metabolic pathways in prostate cancer progression." Thesis, Queensland University of Technology, 2011. https://eprints.qut.edu.au/49029/1/Amy_Lubik_Thesis.pdf.
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Prostate cancer (CaP) is the most commonly diagnosed cancer in males in Australia, North America, and Europe. If found early and locally confined, CaP can be treated with radical prostatectomy or radiation therapy; however, 25-40% patients will relapse and go on to advanced disease. The most common therapy in these cases is androgen deprivation therapy (ADT), which suppresses androgen production from the testis. Lack of the testicular androgen supply causes cells of the prostate to undergo apoptosis. However, in some cases the regression initially seen with ADT eventually gives way to a growth of a population of cancerous cells that no longer require testicular androgens. This phenotype is essentially fatal and is termed castrate resistant prostate cancer (CRPC). In addition to eventual regression, there are many undesirable side effects which accompany ADT, including development of a metabolic syndrome, which is defined by the U.S. National Library of Medicine as “a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.” This project will focus on the effect of ADT induced hyperinsulinemia, as mimicked by treating androgen receptor positive CaP cells with insulin in a serum (hormone) deprived environment. While this side effect is not widely explored, in this thesis it is demonstrated for the first time that insulin upregulates pathways important to CaP progression.
Our group has previously shown that during CaP progression, the enzymes necessary for de novo steroidogenesis are upregulated in the LNCaP xenograft model, total steroid levels are increased in tumours compared to pre castrate levels, and de novo steroidogenesis from radio-labelled acetate has been demonstrated. Because of the CaP dependence on AR for survival, we and other groups believe that CaP cells carry out de novo steroidogenesis to survive in androgen deprived conditions. Because (a) men on ADT often develop metabolic syndrome, and (b) men with lifestyle-induced obesity and hyperinsulinemia have worse prognosis and faster disease progression, and because (c) insulin causes steroidogenesis in other cell lines, the hypothesis that insulin may contribute to CaP progression through upregulation of steroidogenesis was explored.
Insulin upregulates steroidogenesis enzymes at the mRNA level in three AR positive cell lines, as well as upregulating these enzymes at the protein level in two cell lines. It has also been demonstrated that insulin increases mitochondrial (functional) levels of steroid acute regulatory protein (StAR). Furthermore, insulin causes increased levels of total steroids in and induction of de novo steroid synthesis by insulin has been demonstrated at levels induced sufficient to activate AR.
The effect of insulin analogs on CaP steroidogenesis in LNCaP and VCaP cells has also been investigated because epidemiological studies suggest that some of the analogs developed may have more cancer stimulatory effects than normal insulin. In this project, despite the signalling differences between glargine, X10, and insulin, these analogs did not appear to induce steroidogenesis any more potently that normal insulin. The effect of insulin of MCF7breast cancer cells was also investigated with results suggesting that breast cancer cells may be capable of de novo steroidogenesis, and that increase in estradiol production may be exacerbated by insulin.
Insulin has also been long known to stimulate lipogenesis in the liver and adipocytes, and has been demonstrated to increase lipogenesis in breast cancer cells; therefore, investigation of the effect of insulin on lipogenesis, which is a hallmark of aggressive cancers, was investigated. In CaP progression sterol regulatory element binding protein (SREBP) is dysregulated and upregulates fatty acid synthase (FASN), acetyl CoA-carboxylase, and other lipogenesis genes. SREBP is important for steroidogenesis and in this project has been shown to be upregulated by insulin in CaP cells. Fatty acid synthesis provides building blocks of membrane growth, provides substrates for acid oxidation, the main energy source for CaP cells, provides building blocks for anti-apoptotic and proinflammatory molecules, and provides molecules that stimulate steroidogenesis. In this project it has been shown that insulin upregulates FASN and ACC, which synthesize fatty acids, as well as upregulating hormone sensitive lipase (HSL), diazepam-binding inhibitor (DBI), and long-chain acyl-CoA synthetase 3 (ACSL3), which contribute to lipid activation of steroidogenesis. Insulin also upregulates total lipid levels and de novo lipogenesis, which can be suppressed by inhibition of the insulin receptor (INSR). The fatty acids synthesized after insulin treatment are those that have been associated with CaP; furthermore, microarray data suggests insulin may upregulate fatty acid biosynthesis, metabolism and arachidonic acid metabolism pathways, which have been implicated in CaP growth and survival.
Pharmacological agents used to treat patients with hyperinsulinemia/ hyperlipidemia have gained much interest in regards to CaP risk and treatment; however, the scientific rationale behind these clinical applications has not been examined. This thesis explores whether the use of metformin or simvastatin would decrease either lipogenesis or steroidogenesis or both in CaP cells. Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitor, which blocks synthesis of cholesterol, the building block of steroids/ androgens. It has also been postulated to down regulate SREBP in other metabolic disorders. It has been shown in this thesis, in LNCaP cells, that simvastatin inhibited and decreased insulin induced steroidogenesis and lipogenesis, respectively, but increased these pathways in the absence of insulin. Conversely, metformin, which activates AMP-activated protein kinase (AMPK) to shut down lipogenesis, cholesterol synthesis, and protein synthesis, highly suppresses both steroidogenesis and lipogenesis in the presence and absence of insulin.
Lastly, because it has been demonstrated to increase steroidogenesis in other cell lines, and because the elucidation of any factors affecting steroidogenesis is important to understanding CaP, the effect of IGF2 on steroidogenesis in CaP cells was investigated. In patient samples, as men progress to CRPC, IGF2 mRNA and the protein levels of the receptors it may signal through are upregulated. It has also been demonstrated that IGF2 upregulates steroidogenic enzymes at both the mRNA and protein levels in LNCaP cells, increases intracellular and secreted steroid/androgen levels in LNCaPs to levels sufficient to stimulate the AR, and upregulated de novo steroidogenesis in LNCaPs and VCaPs. As well, inhibition of INSR and insulin-like growth factor 1 receptor (IGF1R), which IGF2 signals through, suggests that induction of steroidogenesis may be occurring predominantly through IGF1R.
In summary, this project has illuminated for the first time that insulin is likely to play a large role in cancer progression, through upregulation of the steroidogenesis and lipogenesis pathways at the mRNA and protein levels, and production levels, and demonstrates a novel role for IGF-II in CaP progression through stimulation of steroidogenesis. It has also been demonstrated that metformin and simvastatin drugs may be useful in suppressing the insulin induction of these pathways. This project affirms the pathways by which ADT- induced metabolic syndrome may exacerbate CaP progression and strongly suggests that the monitoring and modulation of the metabolic state of CaP patients could have a strong impact on their therapeutic outcomes.
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Pazaitis, Nikolaos [Verfasser], Stefan [Gutachter] Hüttelmaier, Jan-Henning [Gutachter] Klussmann, and Martin [Gutachter] Pichler. "In vitro und in vivo Untersuchungen zur Tumorigenität des Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) : [kumulative Dissertation] / Nikolaos Pazaitis ; Gutachter: Stefan Hüttelmaier, Jan-Henning Klussmann, Martin Pichler." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2020. http://d-nb.info/122112997X/34.
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Kashyap, Abhishek S. "In vitro functional characterisation of IGF-I : VN-induced breast cancer progression." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/62165/1/Abhishek_Kashyap_Thesis.pdf.
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Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions.
The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive.
Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases.
In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.
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Gebski, Bijanka L. "Investigating TNF inhibition of IGF-1 signalling via JNK in cell culture models of skeletal muscle atrophy." University of Western Australia. School of Anatomy and Human Biology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0097.
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[Truncated abstract] The pro-inflammatory cytokine tumour necrosis factor (TNF) has a critical role in skeletal muscle atrophy. The catabolic effect of TNF is partially due to abrogation of the anabolic insulin-like growth factor 1 (IGF-1) signalling pathway. However, the precise signalling events that lead to the loss of myofibrillar protein following activation of TNF receptor are unknown. The over arching aim of the study is to determine the mechanisms of by which TNF induces atrophy in differentiated muscles cells. To achieve this aim a series of experiments were performed to: 1) investigate the molecular events that lead to TNF mediated myofibre atrophy, 2) determine to what extent c-Jun N-terminal Kinase (JNK) signalling plays a part in TNF induced myotube atrophy, and in TNF-mediated inhibition of IGF-1 induced hypertrophy, and 3) use inhibitors of JNK to block the catabolic effects of TNF. 1) To investigate the molecular events that lead to TNF mediated myofibre atrophy, the experiments were conducted using C2C12 mouse myotube cultures and primary myotube cultures derived from FVB mice, and transgenic mice which over-express Class 2 IGF-1 Ea in skeletal muscles (IGF:C2). The treatment of mature C2C12 and FVB primary myotubes (respectively at 7 and 4 days after fusion medium) with 10 ng/mL of TNF for 3 days resulted in statistically significant myotube atrophy (decreased mean width). The observed TNF-mediated atrophy has not previously been demonstrated in tissue cultured myotubes. In contrast, addition of IGF-1 (20 ng/ml) to 7 day C2C12 myotubes for 3 days resulted in significant hypertrophy. ... The most suitable inhibitor was TAT-TIJIP and was thus used in subsequent studies. Inhibition of JNK activity by TAT-TIJIP was confirmed indirectly by detecting nuclear translocation of c- Jun, which is a downstream target of phosphorylated JNK. Immunohistochemical analyses showed nuclear localisation and phosphorylation of c-Jun in TNF treated myotubes. Nuclear localisation and phosphorylation of c-Jun was not observed in cultures pre-treated with TAT-TIJIP before TNF treatment, nor in the untreated control myotubes. 3) The use of JNK inhibitors to block the catabolic effects of TNF was tested using C2C12 and primary myotube cultures. Pre-treatment of C2C12 and primary FVB myotubes with the JNK inhibitor TAT-TIJIP, 30 min before TNF administration (for 3 days) prevented myotube atrophy. The mean width of myotubes pre-treated with TATTIJIP prior to TNF treatment closely resembled that of the control myotubes. Administration of TNF in combination with TAT-TIJIP for 3 days to C2C12 myotubes prevented myotube atrophy and unexpectedly resulted in hypertrophy when compared to the mean widths of untreated and TAT-TIJIP treated myotubes. This trend was also demonstrated in the FVB primary cultures. These combined results strongly support the role of JNK in TNF-mediated atrophy. Preliminary studies were carried out in vivo using the mdx mouse model of muscular dystrophy, TAT-TIJIP was administered via intraperitoneal injection to the mice for 3 days at a dose of 10 mg/ml, however the results form this study are inconclusive. These novel observations are of considerable interest to the field of muscle wasting because they demonstrate for the first time TNF-mediated myotube atrophy, the role of JNK in situations of TNF induced muscle atrophy, and explore the use of JNK inhibitors to prevent muscle atrophy.
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Hallatschek, Werner. "Die Regulation des humanen Lipopolysaccharid bindenden Proteins (hLBP)." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15202.
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Das Lipopolysaccharid Bindende Protein (LBP) ist ein überwiegend in der Leber synthetisiertes Akutphaseprotein. Es bindet den Zellwandbestandteil Lipopolysaccharid (LPS) Gram-negativer Bakterien und transportiert es zu zellulären Rezeptoren, wodurch das angeborene Immunsystem aktiviert wird. In dieser Arbeit wird die Regulation der LBP-Expression in Interleukin (IL)-1, IL-6 und Dexamethason (Dex) stimulierten humanen Hepatomzelllinien HuH-7 und HepG2 untersucht. Der wichtigste Stimulator ist dabei IL-6, dessen Wirkung über die Transkriptionsfaktoren (TF) Stat-3, C/EBP-beta und AP-1 vermittelt wird. Für alle 3 TF konnten aktive Bindungsstellen auf dem LBP-Promotor nachgewiesen werden. Für IL-1-Effekte die u. a. über den TF NF-kappaB vermittelt werden, konnten ebenfalls aktive Bindungsstellen nachgewiesen werden. Die Wirkung von Dex wird über Glucocorticoid Responsive Elements (GREs) vermittelt. Auf dem LBP-Promotor befinden, sich wie gezeigt werden konnte, mehrere aktive GREs, wobei einige verstärkend und einige hemmend wirken. Eine zu beobachtende Synergiewirkung von Dex und IL-6 wird durch die Aufregulation des IL-6-Rezeptors durch Dex verursacht. Die LBP-Expression kann durch TGF (Transforming Growth Factor)-beta gehemmt werden. Der TGF-beta-Signalweg über Smads ist in den Hepatomzellen aktiv, vermittelt aber nicht den TGF-beta-Hemmeffekt, sondern eine geringe stimulierende Wirkung, die bei alleiniger TGF-beta-Inkubation auftritt. Die inhibierende Wirkung von TGF-beta wird durch Gfi-1- und AP-1-Bindungsstellen vermittelt. Die Gfi-1-Bindungsstelle nimmt dabei, wie hier erstmals gezeigt werden konnte, eine herausragende Stellung ein. Die Aufklärung der LBP-Regulation und dabei besonders die Hemmung der LBP-Expression kann mittelfristig dazu beitragen, den klinischen Verlauf von inflammatorischen und infektiösen Erkrankungen zu beeinflussen und bietet daher Potenzial für neue Therapieansätze.Lipopolysaccharide (LPS) binding protein (LBP) is an acute phase protein with the ability to bind and transfer LPS of Gram-negative bacteria. This soluble pattern recognition molecule represents an important defense principle of the host. Regulation of the hepatic acute phase response and its termination are important mechanisms for limiting systemic inflammatory activity of the host. Here were analyze the cooperation of Interleukin (IL)-1, IL-6, and Dexamethasone (Dex) at LBP expression in the hepatoma cell lines HuH-7 and Hep G2. The major inducer of LBP expression is IL-6. Within the LBP promoter numerously highly consensus binding sites such as AP-1, C/EBP-beta? and STAT3 are present, that confer transcriptional activity as shown by truncation and mutation experiments. Additionally, activate NF-kappaB sites activated by IL-1 were detected at the LBP promoter. By mutation experiments of the promoter furthermore were found differentially active glucocorticoid response elements (GREs). The promoter contains GREs enhancing the activity as well as inhibitory ones. The enhancing effect towards LBP expression by Dex was mediated by IL-6. Dex stimulated the expression of the IL-6 receptor and therefore upregulated the IL-6 pathway. Transforming Growth Factor (TGF)-beta is able to inhibit LBP expression in stimulated cells. An AP-1 binding site was identified mediating inhibitory TGF-beta effects towards LBP promoter activity. Furthermore it was shown that a growth factor independence (Gfi)-1 binding site localized near the AP-1 site is essential for mediating the TGF-beta inhibitory effect. The relevancy of the Gfi-1 site fore mediating TGF-beta effects indicates a novel mechanism for understanding inhibitory TGF-beta effects at the transcriptional level. In summary the complex regulation of LBP were elucidate which may help to eventually develop novel intervention strategies for acute phase, sepsis, and septic shock.
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Pelletier, Sanja [Verfasser], Yves [Gutachter] Garnier, and Angela [Gutachter] Kribs. "Differenzierte Therapie der drohenden spontanen Frühgeburt bei Einlingsschwangerschaften unter Berücksichtigung des phosphorylierten insulin-like growth-factor binding protein-1 (phIGFBP-1) im Zervikalsekret und der sonographisch gemessenen Zervixlänge Eine multizentrische prospektive Kohortenstudie : eine multizentrische prospektive Kohortenstudie / Sanja Pelletier ; Gutachter: Yves Garnier, Angela Kribs." Köln : Deutsche Zentralbibliothek für Medizin, 2021. http://d-nb.info/1229194835/34.
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Cunha, Angela Francisca Trinconi da. "Avaliação dos fatores de crescimento insulinóides IGF-1 e IGFBP-3 em mulheres com alto risco para câncer de mama." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-04112010-141608/.
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INTRODUÇÃO: A crescente incidência de câncer de mama, que cada vez mais acomete mulheres jovens, tem despertado muito interesse no diagnóstico precoce e na busca do tratamento mais eficaz e minimamente agressivo. Da mesma forma, vem aumentando a parcela da população com alto risco para câncer de mama, para a qual as atenções têm se voltado no sentido de se encontrar um caminho que permita prevenir o surgimento da neoplasia. Inspirados por Peyrat, que primeiro associou o câncer de mama com a presença de fator de crescimento insulina like tipo 1 (IGF-1), vários autores se lançaram nesta procura e, apesar de controversa, a literatura internacional tende a mostrar uma relação direta entre IGF-1 e câncer de mama na pré-menopausa. A proteína carreadora de IGF do tipo 3, ou IGFBP-3, também foi adicionada ao rol de sustâncias com possibilidade de promover câncer, porém, não tem demonstrado clara regularidade em seu mecanismo de ação. Tendo como alvo a população com alto risco para câncer de mama, quer histopatológico, quer familiar, e direcionada pelos cálculos matemáticos de Gail e Tyrer-Cuzick, essa tese objetivou avaliar a relação entre IGF-1 e IGFBP-3 em mulheres brasileiras atendidas pelo Setor de Mastologia da Disciplina de Ginecologia do Departamento de Obstetrícia e Ginecologia da Faculdade de Medicina da Universidade de São Paulo. MÉTODOS: estudo transversal em que foram comparados os níveis séricos de IGF-1 e IGFBP-3, dosados pelo método imunométrico quimioluminescente, em 3 diferentes grupos: mulheres com câncer de mama não tratado (n= 51), mulheres com risco populacional (n= 66) e mulheres com alto risco para câncer de mama (n= 108). Foram considerados fatores de comparação: idade, estado menopausal e índice de massa corpórea. RESULTADOS: 1) não houve diferenças entre os grupos com respeito ao IMC; 2) foi estatisticamente significativa a diferença das médias de idades dos grupos, sendo as mulheres com alto risco para câncer de mama mais jovens (p<0,001); 3) quanto ao estado menopausal, houve significativa diferença entre os grupos, com predomínio de mulheres pós-menopausa no grupo de pacientes com câncer de mama (58,8%), com p <0,001; 4) não foi encontrada relação estatisticamente significante entre percentual de IGF-1 em relação à mediana, percentual de IGFBP-3 em relação à mediana e razão dos percentuais de IGF-1 e IGFPB-3 em relação à mediana para os 3 grupos estudados;4) não houve variações nas dosagens de acordo com o tipo de situação determinante do alto risco para câncer de mama (familiar ou histopatológico); 5) não houve alteração estatisticamente significativa das variáveis estudadas, mesmo após subdivisão do grupo de alto risco (risco vitalício entre 20 e 29% X risco vitalício superior a 29%). CONCLUSÃO: Não foi observada variação dos níveis séricos de IGF-I e IGFBP-3 em mulheres com câncer de mama, com alto risco para câncer de mama ou com risco populacionalINTRODUCTION: The rising incidence of breast cancer, a disease that is increasingly affecting young women, has aroused a great deal of interest in early diagnosis and the search for a more efficient and minimally aggressive treatment. Likewise, the population at high risk for breast cancer has been growing, and it is now the focus of research efforts in the struggle to prevent neoplasia. Inspired by Peyrat, who was the first to associate breast cancer with insulin-like growth factor type 1 (IGF-1), several authors have taken on the challenge, and the international literature now leans towards a direct relationship, albeit still controversial, between IGF-1 and breast cancer in premenopause. The IGF binding protein 3 (IGFBP-3) has also been added to the list of cancer-causing agents, but its mechanism of action has not shown to be clearly regular. Targeting a population at high risk for breast cancer for histopathologic or familial reasons, and guided by the mathematical calculations of Gail and Tyrer-Cuzick, this thesis aimed at evaluating the relationship between IGF-1 and IGFB-3 in Brazilian female outpatients at the Mastology Sector of the Gynecology Discipline of the Department of Obstetrics and Gynecology of the School of Medicine of the University of São Paulo. METHODS: Transverse study to compare the serum levels of IGF-1 and IGFBP- 3 measured by the chemiluminescent immunometric method. The patients were divided into 3 different groups: women with untreated breast cancer (n=51), women with a population-based risk of breast cancer (n=66), and women at high risk for breast cancer (n=108). The comparison factors were age, menopausal state, and body mass index. RESULTS: 1) there were no differences among the groups with respect to BMI; 2) but there were statistically significant differences among the groups regarding mean age, and the younger women were those at a higher risk for breast cancer (p<0.001); 3) as for menopausal state, the groups were significantly different, and the postmenopausal women were prevalent among the patients with breast cancer (58.8%; p<0.001); 4) no statistically significant relationship was found between the IGF-1 percentage and the median, the IGFBP-3 percentage and the median, or the IGF-1 and IGFBP-3 ratio and the median in any of the groups; 5) measurements did not vary according to the determinant reason for high breast cancer risk (familial or histopathologic); 6) statistically significant changes in the variables under consideration did not take place, even after subdivision of the high-risk group (lifelong risk between 20% and 29% X lifelong risk over 29%). CONCLUSION: The serum levels of IGF-I and IGFBP-3 showed no variation among women with breast cancer, at high risk for cancer, or with populationbased risk
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Zhang, Fan. "Receptor-operated signaling pathways in normal and diabetic pancreatic islet cell function /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-006-0/.
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Bradburn, Jennifer Elizabeth. "Reactive species promotion of head and neck squamous cell carcinoma." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1166555968.
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Giroto, Alan Brunholi. "Adição de proteína plasmática a associada à prenhez (PAPP-A) durante a maturação in vitro aumenta o IGF-1 biodisponível e modula o perfil transcricional de complexos cumulus-oócitos e embriões bovinos." Universidade do Oeste Paulista, 2018. http://bdtd.unoeste.br:8080/jspui/handle/jspui/1091.
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In this study we aimed to evaluate how PAPP-A addition during in vitro maturation affected the IGF-1 quantification, transcript abundance related to cumulus oocyte complexes (COCs) and blastocysts quality, embryonic yield, as well as post-warming survival. We matured COCs through a 24 h treatment of TCM199 serum-free medium, either with PAPP-A supplementation (100 ng/mL; PAPP-A group) or without (control). Maturation medium was collected for IGF-1 quantification, and matured COCs were used for in vitro fertilization and culturing. The PAPP-A group exhibited 1.27 times higher IGF-1 concentrations than control. A comparison of in vitro embryo production across the groups found no difference in cleavage rate, embryonic yield, and survival, 3 and 24 h post-cryopreservation. In PAPP-A oocytes, only TXNRD1 was up-regulated. However, in PAPP-A cumulus cells, VNN1 and HDAC2 were up-regulated, while AGPAT1, AGPAT9, FASN, CASP3, EGFR, HAS2, IMPDH1, and MTIF3 were down-regulated. Finally, in PAPP-A blastocysts, CPT2, CASP9, DNMT3A, TFAM, and KRT8 were up-regulated, while ATF4, CASP3, and IFITM3 were down-regulated. We concluded that PAPP-A addition increased IGF-1 but did not influence embryonic yield and survival. Nevertheless, elevated IGF-1 could improve embryo competence through modulating expression of genes involved with lipid metabolism, oocyte competence and apoptosis in COCs and blastocysts.
A protéina sérica associada à prenhez (PAPP-A) é capaz de modular a biodisponibilidade do IGF-1 (fator de crescimento semelhante à insulina tipo 1) pela quebra das ligação com as proteínas de ligação do IGF (IGFBPs). O objetivo foi avaliar como a adição da PAPP-A durante a maturação in vitro (MIV) afetou a biodisponibilidade de IGF-1, a abundância de transcritos nos oócitos e células do cumulus e blastocistos, a produção embrionária e a sobrevivência pós aquecimento. Foi realizada a MIV de 24 h em complexos cumulus oócitos (CCOs – 20/grupo) oriundos de abatedouro, em meio TCM199 livre de soro, com adição de PAPP-A (100 ng/mL; grupo PAPP-A) ou sem (controle). O IGF-1 foi quantificado no meio de maturação e os CCOs maturados foram utilizados na fertilização e cultivo in vitro. Oócitos e células do cúmulus foram separados; e blastocistos foram congelados para a realização da expressão gênica. Taxa de clivagem e produção de blastocistos foram calculados como porcentagem e transformados para arco seno. Dados de expressão gênica foram normalizados com a média do grupo de controle. Os resultados foram analisados por test t, porém a criopreservação embrionária foi testada por Qui-quadrado (JMP software, SAS). Diferenças foram consideradas significativas quando p ≤ 0,05. O grupo PAPP-A apresentou 27% mais concentração de IGF-1 biodisponível. Na produção in vitro de embriões, não encontrou-se diferença na taxa de clivagem, produção e sobrevivência embrionária. Apenas o gene TXNRD1 mostrou maior expressão nos oócitos do grupo PAPP-A. No entanto, nas células do cumulus PAPP-A, o VNN1 e HDAC2 apresentaram maior expressão, enquanto os genes AGPAT1, AGPAT9, FASN, CASP3, EGFR, HAS2, IMPDH1 e MTIF3 apresentaram menor expressão. Nos blastocistos PAPP-A, os genes CPT2, CASP9, DNMT3A, TFAM e KRT8 apresentaram maior expressão, enquanto os genes ATF4, CASP3 e IFITM3 apresentaram menor expressão. Em conclusão, a adição de PAPP-A durante a MIV aumentou o IGF-1 biodisponível, mas não influenciou a produção e a sobrevivência embrionária após desvitrificação. No entanto, o aumento do IGF-1 biodisponível pode melhorar a competência embrionária através da modulação da expressão gênica em oócitos, células do cúmulus e blastocistos.
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Zabihi, Sheller. "Fetal Outcome in Experimental Diabetic Pregnancy." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8739.
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Women with pregestational diabetes have a 2-5 fold increased risk of giving birth to malformed babies compared with non-diabetic women. Diabetes-induced oxidative stress in maternal and embryonic tissues has been implicated in the teratogenic process. The malformations are likely to be induced before the seventh week of pregnancy, when the yolk sac is partly responsible for the transfer of metabolites to the embryo, and the uterine blood flow to the implantation site determines the net amount of nutrients available to the conceptus. We aimed to evaluate the effect on embryogenesis caused by a diabetes-induced disturbance in yolk sac morphology, uterine blood flow or altered maternal antioxidative status in conjunction with a varied severity of the maternal diabetic state.
We investigated to which extent maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes (SOD, CAT, GPX), vascular endothelial growth factor-A (Vegf-A), folate binding protein-1 (Folbp-1), and apoptosis associated proteins (Bax, Bcl-2, Caspase-3) in the yolk sacs of rat embryos on gestational days 10 and 11. We found that maternal diabetes impairs, and that FA supplementation restores, yolk sac vessel morphology, and that maternal diabetes is associated with increased apoptotic rate in embryos and yolk sacs, as well as impaired SOD gene expression. We assessed uterine blood flow with a laser-Doppler-flow-meter and found increased blood flow to implantation sites of diabetic rats compared with controls. Furthermore, resorbed and malformed offspring showed increased and decreased blood flow to their implantation sites, respectively. In mice with genetically altered CuZnSOD levels, maternal diabetes increased embryonic dysmorphogenesis irrespective of CuZnSOD expression. We thus found the maternal diabetic state to be a major determinant of diabetic embryopathy and that the CuZnSOD status exerts a partial protection for the embryo in diabetic pregnancy.