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Dissertations / Theses on the topic 'Insulin-like growth factor binding protein'

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Published: 4 June 2021

Last updated: 7 September 2023

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1

Robertson, James Gray. "Insulin-like growth factors and insulin-like growth factor binding proteins in wounds /." Title page, contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phr6509.pdf.

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2

Jones, Tiffany Celeste. "Syndecan-4 binds insulin-like growth factor binding protein-4." Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/jones.pdf.

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3

Twigg, Stephen Morris. "Insulin-like growth factor binding protein-5 and its complexes." Thesis, The University of Sydney, 1998. https://hdl.handle.net/2123/27686.

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The insulin-like growth factors, IGF-I and IGF-H, are multifunctional proteins. They are anabolic and they regulate glycaemia, and at tissue and cellular level, IGFs are mitogenic and anti—apoptotic and they may modify differentiated cell function. In serum and tissues IGF bioactivity is modified by six well characterised insulin-like growth factor binding proteins (IGFBPs), that have high affinity for IGF-I and IGF-II.

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4

Wang, Jing. "Novel insulin-like growth factor-binding protein proteases: detection and characterization /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-942-4/.

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5

Ahlsén, Maria. "Insulin-like growth factor binding protein-3 : structure and function /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-350-4/.

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6

Milner, Steven John. "The oxidative folding of insulin-like growth factor-I analogues /." Title page, table of contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phm65945.pdf.

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7

Alsabban, Abdulrahman Essam. "Establishing methods to screen novel small molecules targeting insulin-like growth factor/insulin-like growth factor binding protein interaction." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45046.

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Insulin-like growth factors (IGFs) are important systemic mediators of growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis and metastatic activities in various cancers by activating IGF-IR tyrosine kinase-mediated signaling. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). Increased IGFBP-2 and IGFBP-5 expression observed in castration-resistant prostate cancer is thought to promote tumor progression by enhancing IGF-mediated signaling. IGFBPs have cooperative carboxy-terminal and amino-terminal low and a high affinity IGF binding sites. I hypothesize that blocking the high affinity IGF binding site can affect the bioavailability of IGFs to target tissues and thus be used for treatment of various IGF-responsive diseases including prostate cancer. I initially characterized immunologic reagents capable of being used in sandwich ELISA formats to detect IGF-I and IGFBP-5 and attempted several configurations to establish an IGF-I/IGFBP-5 “bridged” sandwich ELISA platform to measure association and dissociation of IGF-I/IGFBP-5 complex formation. The inability of all bridged ELISA formats tested to measure IGF-I/IGFBP-5 binding, lead me to developed a Bio-Layer Interferometry-based assay that measures IGF-I/ IGFBP-5 binding kinetics that will allow for screening of factors that can affect this intermolecular interaction. I demonstrated that biotinylated IGF-I bound to streptavidin-coated biosensors can be used to measure binding of recombinant IGFBP-5 [2.24 nm shift in optical density (Response)]. I also demonstrated that IGF-I could efficiently disrupt this interaction (0.21 nm shift), while the amino-terminal IGF-I mutant, E3R, exhibits an intermediate competitive activity (1.47 nm shift) and insulin exhibits a low competitive activity (1.83 nm shift). In addition, I demonstrated that IGF-I can competitively disrupted this interaction, resulting in a dissociation rate constant (Kdis 1.5-³ 1/s), In contrast, the amino terminal IGF-I mutant, E3R binds with an intermediate affinity (Kdis 5.6-⁴ 1/s), and buffer free sample results in a (Kdis) of 1.5-⁴ (1/s). These results demonstrate the capacity of this BLI-based assay to differentiate relative competitive activity of compounds that target the high affinity IGF-I binding site of IGFBPs and establish a platform to screen for factors that might be developed as rationale therapeutics to disrupt sequestration of IGF-I by IGFBPs.

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8

Watanabe, Shin. "Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin." Kyoto University, 2011. http://hdl.handle.net/2433/142074.

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9

Balderson, Stephanie D. "Investigations of Insulin-Like Growth Factor I Cell Surface Binding: Regulation by Insulin-Like Growth Factor Binding Protein-3 and Heparan Sulfate Proteoglycan." Thesis, Virginia Tech, 1997. http://hdl.handle.net/10919/30494.

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The primary aim of this text is to gain insight on how cellular activation by a insulin-like growth factor (IGF-I), in the presence of insulin-like growth factor binding protein-3 (IGFBP-3), is influenced by heparan sulfate proteoglycans (HSPG). Initial research will be presented, assumptions and hypotheses that were included in the development of mathematical models will be discussed, and the future enhancements of the models will be explored. There are many potential scenarios for how each component might influence the others. Mathematical modeling techniques will highlight the contributions made by numerous extracellular parameters on IGF-I cell surface binding. Tentative assumptions can be applied to modeling techniques and predictions may aid in the direction of future experiments. Experimentally, it was found that IGFBP-3 inhibited IGF-I Bovine Aortic Endothelial (BAE) cell surface binding while p9 HS slightly increased IGF-I BAE cell surface binding. IGFBP-3 has a higher binding affinity for IGF-I (3 x 10-9 M) than p9 HS has for IGF-I (1.5 x 10-8 M) as determined with cell-free binding assays. The presence of p9 HS countered the inhibiting effect of IGFBP-3 on IGF-I BAE cell surface binding. Although preliminary experiments with labeled p9 HS and IGFBP-3 indicated little to no cell surface binding, later experiments indicated that both IGFBP-3 and p9 HS do bind to the BAE cell surface. Pre-incubation of BAE cells with either IGFBP-3 or p9 HS resulted in an increase of IGF-I BAE cell surface binding . There was a more substantial increase of IGF-I surface binding when cells were pre-incubated with IGFBP- 3 than p9 HS. There was a larger increase of IGF-I BAE cell surface binding when cells were pre-incubated with p9 HS than when p9 HS and IGF-I were added simultaneously. This suggests that IGFBP-3 and p9 HS surface binding plays key role in IGF-I surface binding, however, p9 HS surface binding does not alter IGF-I surface binding as much as IGFBP-3 surface binding seems to. Experimental work helps further the understanding of IGF-I cellular activation as regulated by IGFBP-3 and p9 HS. Developing mathematical models allows the researcher to focus on individual elements in a complex systems and gain insight on how the real system will respond to individual changes. Discrepancies between the model results and the experimental data presented indicate that soluble receptor inhibition is not sufficient to account for experimental results. The alliance of engineering analysis and molecular biology helps to clarify significant principles relevant to the conveyance of growth factors into tissue. Awareness of the effects of individual parameters in the delivery system, made possible with mathematical models, will provide guidance and save time in the design of future therapeutics involving growth factors.
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10

Clark, Sarah Jane. "The growth hormone, insulin-like growth factor, insulin-like growth factor binding proteins and insulin axis in acute liver failure." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397943.

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11

Schaffer, Andrea. "Insulin-like growth factor-I, insulin-like growth factor binding protein-3 and the risk of cervical squamous intraepithelial lesions." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=81435.

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Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with an increased risk of several cancers. This case-control study investigated the relationship between IGF-I and IGFBP-3 plasma levels and the risk of squamous intraepithelial lesions (SILs) of the cervix, as well as the risk of HPV infection in women. 366 cases and 366 controls were recruited from five Montreal area hospitals. There was a significantly decreased risk of LSIL for the highest quartile of IGFBP-3 relative to the lowest quartile (Odds Ratio (OR)=0.25, 95% confidence interval (CI) 0.08-0.77), adjusted for age, HPV status and IGF-I. Also, there was a significantly increased risk of being positive for HPV, specifically high-risk types, for the highest quartiles of IGFBP-3 relative to the lowest quartile in controls (OR=4.53, 95% CI 1.33-15.40), adjusted for age and IGF-I. IGF-I was not significantly associated with SILs or HPV infection.

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12

Launchbury, R. "Insulin-like growth factor binding protein-3 and the hyperplastic prostate." Thesis, University of Edinburgh, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.653702.

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The role of insulin-like growth binding-protein-3 (IGFBP-3) was investigated in primary cultures of hyperplastic prostate cells in the hope of identifying novel drug targets. Benign prostatic hyperplasia (BPH) is a disease of the ageing male, the aetiology of which is unknown. Growth factors, such as insulin-like growth factor (IGF) are implicated in stimulating the prostate growth which causes hyperplasia. IGFBP-3 is an inhibitory binding protein, which functions to sequester IGF away from its receptor, but also has an IGF-independent action once fragmented. Cellular proteases, including prostate specific antigen (PSA), fragment IGFBP-3, and the resulting fragments have actions independent of the intact protein. The inhibitory action of fragmented IGFBP-3 has been documented in prostate epithelial cell lines, but there are no reports of its action in stromal cells, which is investigated here. Initially, the endogenous production of IGFBP-3 by primary cultures of stroma and epithelium was investigated. RT-PCR showed expression of IGFBP-3 mRNA in both stroma and epithelium, and immunocytochemistry, and Western blotting on cell lysates, indicated IGFBP-3 protein production in both cell types. The localisation of IGFBP-3 in primary cultures was the same as that observed in sections of hyperplastic and malignant prostate tissue. Western blotting on stromal and epithelial conditioned medium showed fragmentation of endogenous IGFBP-3 by cellular proteases. Proteolysis of IGFBP-3 by PSA produced fragments of 22-25kDa and 15kDa. ELISAs showed a large differential in concentration of IGFBP-3 produced by primary stomal and epithelial cells which affected subsequent growth experiments using exogenous protein. Proliferation experiments showed a non-dose dependent inhibitory response to IGFBP-3 by epithelial cells, probably due to sequestration of IGF. No response was observed in stomal cells to intact or fragmented protein, however, due to the high concentration of endogenous IGFBP-3 produced.

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13

Fowler, Clare Amanda. "Insulin-like growth factor binding protein modulation of breast cancer treatment." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392972.

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14

Hassard, Jennifer. "Mitochondrial membrane binding and protein complexing of the anti-apoptotic adaptor protein Grb10." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33772.

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Grb10 is a member of the Grb7 family of adaptor proteins that also includes Grb7 and Grb14. These three members contain multiple protein binding domains and lack enzymatic activity. Extensive two-hybrid studies have demonstrated binding of Grb10 to numerous activated tyrosine kinase receptors including the insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR), as well as many non-receptor molecules such as MEK1, Raf-1, and Nedd4. Grb10 has been implicated in IGF-I anti-apoptotic signaling regulation through interactions with Raf-1 and the mitochondrial membrane.
In this report the pattern of transient Grb10 translocation following IGF-I cellular stimulation was studied. This report also demonstrates the implication of a short variable amino-terminal region of Grb10 in mitochondrial membrane association. Finally, assays were developed with the goal of identifying new Grb10 binding partners.

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15

Miyamoto, Shinichi. "Matrix Metalloproteinase-7 Facilitates Insulin-like Growth Factor Bioavailability through its Proteinase Activity on Insulin-like Growth Factor Binding Protein-3." Kyoto University, 2004. http://hdl.handle.net/2433/147465.

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16

Hopkins, Nicholas John. "Insulin-like growth factor-I and its binding proteins." Thesis, University of Reading, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240702.

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17

Carrick, Francine Ellen. "Characterization of bovine insulin like growth factor binding protein-2 : structure and function." Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phc3158.pdf.

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18

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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19

Gill, Zahidah Perveen. "Modulation of cellular survival by insulin-like growth factor binding protein-3." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297809.

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20

Shah, Pooja Trusha Mehool. "Insulin-like growth factor binding protein-2 and its role in angiogenesis." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22866/.

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Therapeutic angiogenesis is currently under investigation to restore tissue perfusion in peripheral arterial disease (PAD). However, clinical trials have proved to be disappointing in stimulating the development of functional blood vessels and reducing adverse events. Insulin-like growth factor binding protein-2 (IGFBP-2) has demonstrated potential in proangiogenic activity but the molecular mechanisms remain unestablished. Structurally, IGFBP-2 possesses domains which can interact with insulin-like growth factor (IGF), receptor protein tyrosine phosphatase-β, glycosaminoglycans, integrins and can potentially translocate into the nucleus to activate cellular and pathological processes. In this project, we used two IGFBP-2 over-expressing mouse models, namely a global and an endothelial specific model, to determine whether increasing IGFBP-2 can increase perfusion in an experimental model of ischemia in vivo. The angiogenic potential of IGFBP-2 was investigated in an array of in vitro angiogenic signalling and functionality studies in vascular endothelial cells. Recombinant IGFBP-2 was generated, in which site-directed mutagenesis was employed to disrupt the integrin binding site (RGD), IGF binding site, or the heparin binding domain-1/nuclear localisation signal. These mutants were used to determine the primary mechanism IGFBP-2 may use to exert in vitro angiogenic effects. Upregulation of IGFBP-2 in ischemic muscles was confirmed in wild-type mice following hind limb ischemia surgery. IGFBP-2 over-expression significantly enhanced perfusion at early stages of recovery. In vitro angiogenic signalling and functional assays demonstrated IGFBP-2 increased phosphorylation of Akt and ERK/MAPK, as well as enhancing endothelial cell adhesion, wound closure and tube formation. Site-directed mutagenesis identified the RGD domain to be critical in IGFBP-2-stimulated in vitro angiogenic activity. In contrast to VEGF, exposure of IGFBP-2 to endothelial cells did not affect endothelial monolayer permeability. In conclusion, IGFBP-2, via its RGD domain displays promising potential as a new therapeutic angiogenic treatment.

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21

Lord, Andrew P. D. "IGF transfer from blood to tissue: comparison of IGF-I with analogs that bind poorly to binding proteins, using a vascular perfusion model : a thesis submitted to the University of Adelaide, South Australia, for the degree of Doctor of Philosophy /." Title page, abstract and table of contents, 1993. http://web4.library.adelaide.edu.au/theses/09PH/09phl866.pdf.

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22

Gajanandana, Oraprapai. "Studies of complexes formed in blood in vivo between an insulin-like growth factor analog and binding proteins." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phg145.pdf.

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Includes bibliographical references (43 leaves) This study shows that when LR3IGF-I is administered to animals in pharmacologically active doses, it may be present in either the free form or bound to IGF-binding protein(s) in the circulation. Age and nutrition which are factors that regulate synthesis of endogenous IGF-I and IGF-binding proteins, affect the in vivo formation of complexes between the analog and IGFBP(s). This study also suggests that IGFBP-1 inhibits the pharmacological activity of circulating LR3IGF-I on thymus whereas it appears to stimulate the pharmacological activity of LR3IGF-I in kidneys.

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23

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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24

Mireuta, Matei. "Aspects of insulin-like growth factor binding proteins in cancer." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114128.

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The insulin-like growth factor (IGF) system is composed of two ligands (IGF-1 and IGF-2), two receptors (IGF-1R and IGF-2R) and six binding proteins (IGFBP-1 to -6). IGFs act as endocrine, paracrine and autocrine growth factors and stimulate cell growth, proliferation and metabolism. There is extensive evidence, both from in vitro and in vivo models as well as population studies, that IGF physiology is relevant to neoplasia. IGF-1R is the physiologic receptor for both ligands and its activation elicits a plethora of changes at the cellular level, such as activation of PI3K/AKT/mTOR and Ras/Raf/MAP kinase pathways. Given its role in the maintenance and promotion of neoplasia, the IGF system represents a potential target in the context of cancer therapy.Classically, IGFBPs have been described as carrier proteins for IGFs in the blood and other fluids. They can regulate IGF bioavailability both positively through increases in ligand half-life as well as negatively through competition with the IGF-1R for ligand binding. In addition to their classical roles, there is evidence suggesting that IGFBPs can act independently of IGFs by poorly characterized mechanisms. Additionally, epidemiologic studies have correlated overexpression of certain IGFBPs, in particular IGFBP-2, with poor prognosis in various cancers.Although the role of IGFBPs has been extensively studied in the context of both normal and malignant growth, this thesis describes several new aspects of IGFBPs in neoplasia. In the second chapter, we study the effect of the PI3K/AKT/mTOR cascade on IGFBP-2 gene expression in a breast cancer cell line in vitro. We demonstrate that activation of this pathway essentially leads to an Sp1-dependent increase in IGFBP-2 gene transcription. We further show that Sp-1 is phosphorylated upon PI3K/AKT/mTOR pathway activation and accumulates in the nucleus. In the third chapter, we study the effects of 2-deoxyglucose (2-DG) on IGF-1:IGFBP-3 complex formation. A recent publication suggested that 2-DG unexpectedly disrupted IGF-1:IGFBP-3 binding leading to increases in IGF-1R and AKT signaling in various cell lines. We show by three different techniques that neither 2-DG nor glucose affect IGF-1:IGFBP-3 complex formation. We additionally show that the 2-DG effects observed are not consistent between cell lines and likely the result of changes in intracellular signaling. In the fourth chapter, we study the effects of a novel therapeutic antibody (BI836845) with high affinity for both IGF-1 and IGF-2. In mouse serum samples ex vivo, we show that the addition of BI836845 leads to a shift of IGF-1 from the IGFBPs to the antibody. In vivo, we demonstrate that BI836845 binds the vast majority of IGF-1. Finally, we demonstrate that BI836845 induces a decrease in IGFBP-3 and an increase in growth hormone levels in C57 BL/6 mice.
L'ensemble du système de facteurs de croissance insulinomimétique (IGF) est composé de deux ligands (IGF-1 et IGF-2), de deux récepteurs (IGF- 1R et IGF-2R) et de six protéines de liaison (IGFBP-1 à 6). Les IGFs sont des hormones endocrines, paracrines et autocrines qui stimulent la croissance cellulaire, la prolifération et le métabolisme. Il existe un grand nombre d'études utilisant des approches épidémiologiques ou des modèles in vivo et in vitro qui démontrent l'importance des IGFs dans le contexte du cancer. Le IGF-1R est le récepteur physiologique des deux ligands et son activation mène à d'importants changements cellulaires tels que l'activation des voies de signalisation PI3K/AKT/mTOR et Ras/Raf/MAPK. Étant donné son rôle dans la promotion et dans la progression du cancer, le système des IGFs représente une cible potentielle pour le traitement du cancer. De façon classique, les protéines de liaison IGFBP ont été décrites comme de simples porteurs d'IGFs dans le sang et autres fluides. Les IGFBPs peuvent modifier la biodisponibilité des IGFs de façon positive en augmentant leur demi-vie ou de façon négative due à leur compétition avec le IGF-1R pour la liaison. En plus de leur rôle classique, il est de plus en plus évident que ces protéines peuvent agir de manière indépendante, mais les mécanismes impliqués restent flous. Également, il existe des études épidémiologiques qui ont corrélé la surexpression de IGFBPs, en particulier IGFBP-2, avec un pronostic défavorable dans plusieurs formes de cancer. Bien que le rôle des IGFBPs ait été largement étudié dans le contexte de la croissance normale et en néoplasie, la présente thèse révèle quelques nouveaux aspects de la physiologie des IGFBPs dans le contexte du cancer. En première partie, nous étudions l'effet de la voie de signalisation PI3K/AKT/mTOR sur l'expression du gène IGFBP-2 dans une lignée cellulaire de cancer du sein. Nous démontrons que l'activation de cette voie mène essentiellement à une augmentation de la transcription de ce gène de manière dépendante au facteur de transcription Sp-1. De plus, nous établissons que Sp-1 est phosphorylé par l'activation de la voie PI3K/AKT/mTOR et s'accumule dans le noyau. En deuxième partie, nous étudions les effets de la molécule 2-deoxyglucose (2-DG) sur la liaison entre IGF-1 et IGFBP-3. Un récent article avait suggéré un effet inhibitoire de cette molécule sur la formation de complexes IGF -1 :IGFBP-3. Nous démontrons par trois méthodes différentes que 2-DG ou la molécule apparentée glucose n'ont aucun effet sur la liaison entre IGF-1 et IGFBP-3. De plus, nous démontrons que les effets cellulaires de 2-DG sur l'activation de la voie PI3K/AKT/mTOR observées par les auteurs de l'article en question ne sont pas universels et sont probablement le résultat de signaux intracellulaires. Finalement, en dernière partie, nous étudions les effets d'un nouvel anticorps thérapeutique nommé BI836845 qui possède une grande affinité pour IGF-1 et IGF-2. Dans des échantillons de sérum de souris ex vivo, nous démontrons que l'ajout de BI836845 déplace IGF-1 des complexes naturels contenant les IGFBPs vers des complexes contenant l'anticorps. In vivo, nous démontrons que BI836845 lie la grande majorité d'IGF-1. Nous démontrons aussi que l'anticorps mène à une baisse de la concentration de IGFBP-3 et à une hausse de la concentration de l'hormone de croissance chez des souris C57 BL/6.

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25

Niemann, Inga [Verfasser]. "Die Assoziation zwischen Insulin-like Growth Factor I sowie Insulin-like Growth Factor Binding Protein 3 und Knochenumbaumarkern in der Allgemeinbevölkerung / Inga Niemann." Greifswald : Universitätsbibliothek Greifswald, 2016. http://d-nb.info/1115357387/34.

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26

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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27

Cobb, L. J. "Roles of insulin-like growth factor binding protein-5 (IGFBP-5) during myogenesis." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597793.

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Mutation of the N-terminal IGF-binding site of IGFBP-5 and its transfection into myoblasts revealed that the functions of IGFBP-5 in myogenesis can be divided in to IGF-dependent inhibition of myogenesis, and an IGF-independent anti-apoptotic role, assessed by decreased caspase-3 and PARP cleavage, caspase-3 and -9 activities, and decreased annexin V staining of cell populations overexpressing wild type (wtIGFBP-5) and non-IGF binding IGFBP-5 (mutIGFBP-5). Further analysis revealed the decreased apoptosis stimulated by wt and mutIGFBP-5 correlates with increased Bcl-X_Lprotein, and Bad phosphorylation levels. Transfection of myoblasts with wtIGFBP-5 resulted in decreased Akt phosphorylation, increased p38 activation and slightly increased p21 protein levels. Closer examination of cells overexpressing mutIGFBP-5 revealed enhanced myogenesis, increased p38 activation, and slightly, but consistently, increased p21 levels. Intriguingly, increased Akt phosphorylation was also observed in mutIGFBP-5 overexpressing cells which occurred independently of type I receptor activation. This suggests that mutIGFBP-5 was activating an alternative pathway to enhance the myogenic programme. To study the influence of the secretory pathway on the functions of IGFBP-5, the signal peptide was removed (nsIGFBP-5). The overexpression of nsIGFBP-5 in C2 cells had little effect on the rate or extent of myogenesis, Akt phosphorylation or p38 activation when compared with control cells, but increased p21 levels to a greater extent than did wtIGFBP-5. However, more dead cells were visible. When apoptosis was examined in these cell populations, nsIGFBP-5 no longer had a protective effect, as assessed by annexin V staining and caspase-3. Indeed, cells overexpressing nsIGFBP-5 appeared to have slightly elevated apoptosis, and an intriguing 4-fold increase in caspase-9 activation, which was not translated fully in to an increase in caspase-3 activity. The slightly elevated caspase-3 activity interestingly appeared to correlate with an approximate 50% reduction in Bcl-2 protein levels.

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28

Lochrie, Jennifer Dawn. "Insulin-like growth factor binding protein (IGFBP)-5 and mammary epithelial cell function." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433246.

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29

Maile, Laura Ann. "Insulin-like growth factor binding protein-3 proteolysis : in vitro and in vivo." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285815.

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30

Chen, Dong. "Function of Insulin-like Growth Factor Binding Protein 7 (IGFBP7) in Hepatocellular Carcinoma." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2821.

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Title of Dissertation: FUNCTION OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 7(IGFBP7) IN HEPATOCELLULAR CARCINOMA By Dong Chen. Purpose: Hepatocellular carcinoma (HCC) is a highly virulent malignancy with no effective treatment, thus requiring the development of innovative and effective targeted therapies. The oncogene Astrocyte Elevated Gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis and profoundly downregulates Insulin-like Growth Factor Binding Protein-7 (IGFBP7). The present study focuses on analyzing potential tumor suppressor functions of IGFBP7 in HCC and the relevance of IGFBP7 downregulation in mediating AEG-1 function. Experimental Design: IGFBP7 expression was detected by immunohistochemistry in HCC tissue microarrays by real-time PCR and ELISA in human HCC cell lines. Dual Fluorescence in situ hybridization was performed to detect loss of heterozygosity at the IGFBP7 locus. Stable IGFBP7- overexpressing clones were established in the background of AEG-1- overexpressing human HCC cells and were analyzed for in vitro proliferation, senescence, in vivo tumorigenesis and angiogenesis. HCC cell lines infected with an adenovirus expressing IGFBP7 (Ad.IGFBP7) were analyzed by using in vitro cell cycle, apoptosis, in vivo tumorigenesis assays. Results: IGFBP7 expression is significantly downregulated in both human HCC patients’ samples and cell lines compared to normal liver and hepatocytes. IGFBP7 expression was also found to inversely correlate with the stages and grade of HCC. Genomic deletion of IGFBP7 was identified in 26% of HCC patients. Forced overexpression of IGFBP7 in AEG-1 overexpressing HCC cells inhibited in vitro growth and induced senescence. When injected into nude mice, in vivo growth was profoundly suppressed, potentially as a result of inhibition of both angiogenesis and IGF1R activation by IGFBP7. Ad.IGFBP7 profoundly inhibited viability and induced apoptosis in multiple human HCC cell lines by inducing Reactive Oxygen Species (ROS) and activating a DNA damage response. N-acetylcysteine could neutralize ROS and rescue the cells from apoptosis. In early phase after Ad.IGFBP7 infection, activation of cell cycle control proteins like Rb, p53, ATM, ATR, CHK1 and CHK2 were identified and G2/M cell cycle arrest was recorded by FACS. Ad.IGFBP7 infection resulted in the activation of p38 MAPK, and a p38 MAPK inhibitor SB 203580 could block the apoptotic process. In orthotopic xenograft models of human HCC in athymic nude mice, intravenous administration of Ad.IGFBP7 profoundly inhibited primary tumor growth and intra-hepatic metastasis. In a nude mouse subcutaneous model, xenografts from human HCC cells were established in both flanks and only left- side tumors received intratumoral injection of Ad.IGFBP7. Ad.IGFBP7 markedly inhibit growth of both left-sided injected tumors and right-sided un- injected tumors by profound suppression of angiogenesis. Conclusion: The present findings provide evidence that IGFBP7 functions as a novel putative tumor suppressor for HCC and establish the corollary that IGFBP7 downregulation can effectively modify AEG-1 function. Targeted overexpression of IGFBP7 may be a potential novel and effective therapy for HCC.

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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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32

Ferguson, Rhea. "The role of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in the development of cervical squamous intraepithelial lesions." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95203.

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Abstract Objectives: Higher levels of circulating insulin-like growth factor-I (IGF-I) and lower levels of its binding protein (IGFBP-3) have been linked to an increased risk of certain epithelial cancers. It is unclear whether IGF-1 plays a similar role in the development of cervical squamous intraepithelial lesions (SIL). I investigated the association between circulating levels IGF-1 and IGFBP-3 and development of SIL. Methods: Blood serum samples from a nested case-control study were analyzed. Two controls were age and risk-set matched to each case. Conditional logistic regression was used for the statistical analysis and potential confounders, such as age, education, salary and smoking history were included in the model. Results: While the odds ratios of higher quartiles of circulating IGF-1 showed a higher risk of developing SIL, as compared to baseline, none of the associations were significant. The same was found for both IGFBP-3 and the molar ratio IGF-1:IGFBP-3. Conclusions: IGF-1 and IGFBP-3 may play at most a minor role in the development of cervical SIL.
Objectifs: Des niveaux élevés de circulation du facteur de croissance analogue à l'insuline (IGF-I) et des niveaux inférieurs de sa protéine de liaison (IGFBP-3) sont associés à un risque accru de certains cancers épithéliaux, mais leur rôle dans le développement lésions squameuses intraépithéliales cervicales (SIL) demeure incertain. L'association entre les taux circulatoires d'IGF-1 et d'IGFBP-3 et le développement de SIL a été évaluée. Méthodes: Des échantillons de sérum sanguin d'une étude cas-témoins nichée dans une cohorte ont été analysés. Deux sujets du groupe contrôle ont été pairés quand à l'âge et certains facteurs de risque à chaque cas. L'analyse statistique a été effectuée par régression logistique conditionnelle. Résultats: Bien que les rapports de cotes des quartiles supérieurs d'IGF-1, d'IGFBP-3 et le rapport molaire IGF-1: l'IGFBP-3 suggèrent un risque accru de développer des SIL, par rapport aux valeurs initiales, aucune des associations ne sont statistiquement significatives. Conclusions: IGF-1 et IGFBP-3 pourraient jouer tout au plus un rôle mineur dans le développement de SIL du col de l'utérus.

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33

Lucic, Melinda Robin. "Characterisation of the molecular interactions between insulin-like growth factors and their binding proteins." Title page, contents and abstract only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phl9375.pdf.

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Addenda inserted in back. Includes bibliographical references (leaves 139-160) Assesses the importance of amino acids 221 to 236 of bIGFBP-2 for IGF binding activity, by creating amino acid substitutions.

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34

Nickerson, Tara. "A role for insulin-like growth factor binding proteins in apoptosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0022/NQ50229.pdf.

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35

Weber, Miriam S. "The Role of Insulin-like Growth Factor-I and IGF-binding Proteins in Mammary Gland Development." Diss., Virginia Tech, 1998. http://hdl.handle.net/10919/29457.

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Development of the mammary gland is likely mediated by locally produced growth factors acting in concert with circulating mitogens. To investigate the importance of mammary synthesis of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBP), the initial objective was to evaluate the physiological effects of recombinant IGF-I synthesis in the mouse mammary gland. Expression of recombinant IGF-I was targeted by the mouse mammary tumor virus - long terminal repeat (MMTV-LTR) to the mammary glands of two lines (15 and 29) of transgenic mice. Mammary synthesis of recombinant IGF-I increased the frequency of appearance of mammary alveolar buds (71% vs. 21%) in transgenic compared with non-transgenic CD-1 mice. During lactation, mammary synthesis of recombinant IGF-I reduced the amount of endogenous native IGF-I secreted into milk of transgenic mice. Regardless of transgenesis, a shift in the milk IGFBP profile from predominantly IGFBP-3 to a lower molecular weight IGFBP occurred between d 8 and d 12 of lactation. The altered composition of milk from transgenic line 29 dams reduced by 27% the average daily gain of suckling litters, compared with CD-1 dams. Moreover, mammary glands of transgenic mice were less regressed after weaning than controls and were characterized by the presence of more organized secretory lobules. The second overall objective was to evaluate the regulation and physiological effects of mammary IGF-I and IGFBP synthesis in prepubertal heifers. Serum and extracts of mammary tissue at 5% concentration in media stimulated DNA synthesis 545% and 28%, respectively, in primary mammary epithelial organoids in collagen gel culture. Addition of IGFBP-3 strongly inhibited this growth response. High feeding level tended to increase IGFBP-3 levels in mammary tissue and reduced by 30% the growth response to mammary tissue extracts. Somatotropin increased the mitogenic response to mammary extracts at high feeding level and increased the tissue content of IGF-I by 46%. In summary, local synthesis of IGF-I and IGFBP is influenced by feeding level and exogenous somatotropin and contributes substantially to effects on mammary cell proliferation. Interactions of locally produced IGFBP-3 with IGF-I and other growth factors appear to be especially important when mammary growth is modulated by feeding level.
Ph. D.

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36

Zazzi, Henric. "Human insulin-like growth factor binding protein -4 and -6 : gene structure and transcription regulation /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-3873-3/.

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37

Gustafsson, Sara. "The insulin-like growth factor system - effects of circulating proteases /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-436-8/.

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38

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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39

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." Queensland University of Technology, 2008. http://eprints.qut.edu.au/16670/.

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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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40

Lohr, Johannes [Verfasser]. "Die Assoziation des Insulin-like growth factor I und des Insulin-like growth factor binding Protein 3 mit Entzündungsmarkern : Ergebnisse einer bevölkerungsbasierten Studie / Johannes Lohr." Greifswald : Universitätsbibliothek Greifswald, 2017. http://d-nb.info/1143064615/34.

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41

Cassino, Theresa Rachel. "Quantification of the Binding of Insulin-like Growth Factor-I (IGF-I) and IGF Binding Protein-3 (IGFBP-3) Using Surface Plasmon Resonance." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/33531.

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Insulin-like growth factor-I is a small growth factor known to signal in a variety of mammalian cells through the IGF-I cell surface receptor (IGF-IR). A unique feature of the IGF-I system is the regulation of this binding by soluble IGF binding proteins. Recent studies from our laboratory show that there is a pH dependence in the association of IGF-I with the cell surface in the presence of IGFBP-3 which suggested increased association of IGF-I with IGFBP-3 at low pH. We studied cell free interaction of IGF-I and IGFBP-3 as a function of pH using surface plasmon resonance (SPR) in order to understand the mechanism that causes the increased association. In our studies three different SPR instruments with different surfaces for immobilization of one of the binding partners were used: a Leica Bio-SPR 9000 with a low molecular weight carboxymethylated dextran (CMD) surface, a BIAcore 2000 with a high molecular weight CMD surface and a Leica SPR 2001 Alpha with a planar mixed self-assembled monolayer (mSAM) surface. Since the experimental system we used was transport sensitive, only the mSAM surface, under optimized conditions, produced results that fit to a single site model. Results suggest that use of CMD layers for immobilization of one partner of a high-affinity binding complex can result in transport limited binding for which simple analysis is inappropriate. Future studies are planned to expand the work with the mSAM surface to elucidate whether a significant difference between the binding parameters as a function of pH exists.
Master of Science

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42

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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43

Drozd, Anja Christina. "Mechanisms of insulin-like growth factor binding protein-5 (IGFBP-5) action during myogenesis." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611613.

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44

Bramani, Silvia. "A mutagenic and biological study of rat insulin-like growth factor-binding protein-2." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312508.

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45

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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46

de, los Rios Patricia. "Insulin-like growth factor binding proteins (IGFBPs) in ovine fetal growth plate chondrocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0011/MQ28557.pdf.

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47

Kallincos, Nicholas Campbell. "Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in vivo: investigation via transgenesis in rats /." Adelaide : Thesis (Ph.D.) -- University of Adelaide, Department of Biochemistry, 1993. http://web4.library.adelaide.edu.au/theses/09PH/09phk143.pdf.

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48

Chan, Yue-sin. "Insulin-like growth factor I and linear growth at birth to five days in rats." Thesis, Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B24873354.

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49

Martin, Katrin. "Untersuchungen der Insulinähnlichen Wachstumsfaktoren IGF-I und IGF-II, deren Bindeproteine IGFBP-2 und IGFBP-3 und der Säurelabilen Untereinheit ALS bei Kindern mit soliden Tumoren." [S.l. : s.n.], 2007.

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50

Hobba, Graham D. "Studies to identify and characterise IGF-binding determinants of IGFBP-2 /." Title page, contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phh6814.pdf.

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