Dissertations / Theses on the topic 'Insulin-like growth factor'
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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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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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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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Mörth, Corinna. "Consequences of postnatal insulin-like growth factor II overexpression in insulin-like growth factor I deficient mice." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-46307.
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Burns, Jason Lee. "Growth control by insulin-like growth factor II." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270285.
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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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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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Glassford, Janet. "Regulation of insulin-like growth factor-I bioactivity." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624728.
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Holmes, Robert. "The maternal insulin-like growth factor system and fetal growth." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265467.
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Dickey, Lindsey Ann. "Peripheral Hormone Interactions with the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) System in Rainbow Trout." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/31353.
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The growth of vertebrates is primarily regulated by the growth hormone-insulin-like growth factor (GH-IGF) system, but not in isolation. The central question of this dissertation was how do other hormones peripheral to the GH-IGF system interact with the system, including feedbacks by GH and IGF themselves on various tissues in rainbow trout (Oncorhynchus mykiss)? The representative hormones selected were thyroxine, cortisol, and the sex steroids testosterone and estrogen, along with GH and IGF. These hormones were chosen because they are known to affect overall growth and development during specific life events, but exactly what target genes and what mechanisms are involved are only at the early stages of being delineated in fish. Liver and gill tissues were selected as representative tissues to assess the in vitro effects on growth-related genes of the GH-IGF system. A total of more than thirty experiments were conducted, including time- and concentration-response, inhibitory studies, hormone combination studies, and radio-receptor binding assays. Hormones were applied to whole tissue cultures and real-time quantitative-PCR was used to measure hormonal effects on GHR, IGF, and IGFR1 genes. Microsomal preparations were treated with selected hormones and radio-labeled GH or IGF. A gamma counter was used to measure receptor-ligand activity. GH and IGF were found to possess autocrine and/or paracrine actions in self-regulating target growth genes. Thyroxine had no direct effects on targeted growth genes but may interact with other molecules or hormones to elicit its effects on growth and development. Cortisol directly influenced target growth genes in a tissue-specific and isoform-specific manner. Finally, sex steroids differentially regulated the growth genes: estradiol inhibited growth genes while testosterone directly stimulated growth genes. These findings contribute to understanding how hormones peripheral to the GH-IGF system interact with the growth system.National Science Foundation grant IOS 0920116 to Dr. Mark Sheridan
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Bray, Jonathan Alexander. "Comparing insulin and insulin-like growth factor-1 signalling in myoblasts." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596876.
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In this study a chimeric receptor system was employed in which the extracellular domain of the TrkC receptor was fused to the intracellular portion of either the insulin (TIR) or IGF-1 (TIGFR) receptor. These chimeric receptors were expressed in separate populations of the skeletal muscle cell line L6. Initial analysis of individual downstream signalling components and assessment of cell proliferation, induced by TIR or TIGFR stimulation revealed little difference between the two chimeras. To more comprehensively screen for potential differences, microarray analysis was used to compare regulation of gene expression by the two chimeric receptors. This led to the identification of several differentially regulated genes. Whilst it was initially hypothesised that skeletal muscle cells might yield several selectively insulin-sensitive genes, the majority of genes selectively regulated by one receptor were preferentially IGF-1 responsive, consistent with previous studies in other cell types. This perhaps reflects the more mitogenic effect of this ligand in vivo, manifest as an increased ability to regulate transcription per se. Of the differentially regulated genes, that encoding Fit-1m was found to be preferentially induced through activation of the TIGFR rather than the TIR. Further characterisation using real-time PCR established that induction of Fit-1 expression required an intact MAPK signalling pathway. Similar effects were observed when the regulation of Fit-1 expression by insulin and IGF-1 was examined. Subsequent work attempted to establish regions of promoter responsible for the preferential induction of Fit-1m expression by IGF-1. Despite defining promoter and putative enhancer regions which are important for Fit-1m transcription, no region was found which confers a response to stimulation with various ligands, including IGF-1. Rather, a high level of constitutive expression was driven by these DNA sequences, suggesting that an IGF-1 response inhibitory factor may control expression of this gene, binding outside the regions examined. Fit-1 joins an increasing list of genes preferentially regulated by the IGF-1R over the IR and provides and end point with which to analyse potential inherent differences in the signalling capacity of these two highly homologous receptors.
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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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Cheetham, Tim D. "The growth hormone/insulin-like growth factor I axis in insulin-dependent diabetes mellitus during adolescence : studies of recombinant human insulin-like growth factor I (rhIGF-I) administration." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34300.
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The fall in insulin sensitivity during adolescence is accentuated in insulin-dependent diabetes mellitus (IDDM) and has been linked to enhanced growth hormone (GH) secretion. The rise in GH release is related to low insulin-like growth factor I (IGF-I) levels and low IGF bioactivity. Abnormalities of the IGF binding proteins (IGFBP's), including low insulin-like growth factor binding protein-3 (IGFBP-3) and elevated insulin-like growth factor binding protein-1 (IGFBP-1) concentrations are also observed. The rise in GH concentrations may lead to increased insulin requirements that cannot easily be met by current treatment regimens and can result in deteriorating blood glucose control. GH release also enhances ketogenesis and has been linked to the development of microvascular complications. The impact of a subcutaneous injection of rhIGF-I (40 mug/kg) on GH concentrations, insulin sensitivity and the IGFBP's was studied in adolescents with IDDM (n=17). A control night was compared with a night when rhIGF-I was administered at 18.00h. Blood samples were taken regularly overnight and glucose concentrations controlled by a variable-rate insulin infusion. GH concentrations on the control night correlated with glycated haemoglobin levels. The administration of rhIGF-I led to a sustained increase in IGF-I levels, IGF bioactivity and reductions in GH secretion and the insulin infusion requirements to maintain euglycaemia. The change in GH secretion was due to reduced pulse amplitude rather than pulse frequency. The attributes assessing GH release correlated with free insulin concentations on control and rhIGF-I nights, and the reduction in GH release was related to the fall in insulin levels. The concentrations of IGFBP-3 did not fall after rhIGF-I as they did during the control study, but IGFBP-1 levels were unchanged. In longer term studies (n=6), daily rhIGF-I administration (40 ug/kg) for one month led to a reduced isophane insulin dose and a fall in glycated haemoglobin concentrations. GH levels were reduced and IGFBP-3 concentrations rose in 5 of the 6 subjects studied. The administration of rhIGF-I may have a therapeutic role in IDDM during adolescence by reducing GH concentrations and increasing insulin sensitivity.
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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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Heinichen, Markus Gerd. "Insulin-like Growth Factor-1, Mechano Growth Factor und Myosin Schwerketten Transformation beim Krafttraining." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-55900.
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Miell, John Patrick. "Glucocorticoid modulation of growth hormone/insulin - like growth factor - 1 relationships." Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386657.
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Edwall, Dan. "Insulin-like growth factor-I in tissue regeneration and growth control." Stockholm : Karolinska Institute, 1993. http://catalog.hathitrust.org/api/volumes/oclc/28296811.html.
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Girnita, Ada. "Targeting insulin-like growth factor-1 receptor in cancer /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-041-9/.
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Levitt, Randy J. "Aspects of insulin-like growth factor physiology in cancer." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111826.
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The insulin-like growth factor (IGF) pathway consists of two ligands (IGF-I and IGF-II), two receptors (IGF-IR and IGF-IIR) and six IGF binding proteins (IGFBP-I through -6). There is considerable evidence from both laboratory and population studies that IGF physiology is relevant to neoplastic growth. For example, it has been shown that IGF-I and/or IGF-II act as mitogens and anti-apoptotic agents for both normal and malignant cells by binding to the IGF-IR and activating downstream signalling pathways. Consistent with this data, IGF-IR inhibition by a variety of strategies inhibits cancer cell proliferation and/or induces apoptosis both in vitro and in animal models of neoplasia. Furthermore, epidemiological studies have demonstrated a positive correlation between serum IGF-I levels and risk of subsequent cancer. Classically, the IGFBPs were considered to be growth inhibitors, as they had a well-defined role in sequestering the mitogens IGF-I and IGF-II, therefore preventing binding and subsequent activation of mitogenic and anti-apoptotic pathways downstream of the IGF-IR. However, increasing evidence indicates that under certain conditions, IGFBPs can act as growth stimulators, and both IGF-dependent and -independent mechanisms have been proposed.Although the roles of the IGFs, IGF-IR and IGFBPs in cancer have been studied extensively, this thesis describes several new links between IGF physiology and neoplasia. In the first section, we demonstrate that IGF-I can attenuate growth inhibition and apoptosis induced by a class of drugs called COX-2 inhibitors in BxPC-3 pancreatic cancer cells. This effect could be attributed to opposite influences of IGF-IR signalling and COX-2 inhibitors on activation of Akt, with IGF-IR signalling increasing activity and COX-2 inhibitors decreasing activity. In the second section, we demonstrate that in 184htert cells, an immortal but untransformed breast epithelial cell line, COX-2 inhibitors can induce IGFBP-3 expression. We go on to show that IGFBP-3 can inhibit growth of this cell line in an IGF-dependent manner, and speculate that this action of COX-2 inhibitors may be relevant to data linking use of this class of drugs to decreased breast cancer risk. In the third section, we demonstrate that the expression of IGFBP-2 in U251 glioma cells is inhibited by the induction of the tumor suppressor PTEN. Furthermore, IGFBP-2 does not effect the growth of this cell line, indicating that published associations between tumor IGFBP-2 expression and grade of glioma may be a result of IGFBP-2 acting as a marker for loss of function of PTEN. In the fourth and final section, we demonstrate that in MDA-MB-231 breast cancer cells, over-expression of IGFBP-2 can enhance growth, indicating that the effect of IGFBP-2 on growth of neoplastic cells is tissue specific. Furthermore, antisense strategies targeting IGFBP-2 mRNA (antisense oligonucleotides and siRNA) can inhibit growth of IGFBP-2-expressing breast cancer cells both in vitro and in vivo.
Taken together, these results extend the existing body of evidence demonstrating that IGF physiology contributes to neoplastic growth, and suggest that strategies to inhibit IGF-IR signalling and/or IGFBP-2 expression may have therapeutic value for some types of cancers.
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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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Williams, Nolann G. "Myostatin regulation of the insulin-like growth factor axis." Pullman, Wash. : Washington State University, 2009. http://www.dissertations.wsu.edu/Thesis/Spring2009/n_williams_042009.pdf.
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Thesis (M.S. in genetics and cell biology)--Washington State University, May 2009.Title from PDF title page (viewed on Apr. 5, 2010). "School of Molecular Biosciences." Includes bibliographical references (p. 39-45).
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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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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.Master of Science
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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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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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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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Horn, Henrik von. "Regulation of insulin-like growth factor-II in human liver /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-880-0/.
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Mukherjee, Sudipto. "Retinal pigment epithelial cells and the insulin-like growth factor system in proliferative vitreoretinopathy." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/mukherjee.pdf.
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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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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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Zhang, Qimin. "Insulin-like growth factor II : cellular effects through different receptors /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2754-5.
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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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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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Treiber, Kimberly Hoffer. "Glucose regulation in Thoroughbred weanlings: Regulation by insulin, growth hormone and insulin-like growth factor-I." Thesis, Virginia Tech, 2003. http://hdl.handle.net/10919/31221.
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Diets rich in hydrolyzable carbohydrates induce a hyperglycemic/insulinemic response and may increase the incidence of metabolic disorders associated with some types of laminitis, exertional rhabdomyolysis and osteochondrosis in horses. This study applied the minimal model of glucose and insulin dynamics to determine the effect of diet on metabolites and hormones that regulate glucose metabolism in young horses. Twelve Thoroughbred foals were raised on pasture and supplemented twice daily with a feed high in either sugar and starch (SS) or fat and fiber (FF). As weanlings (age 199 ± 19 d, weight 274 ± 18 kg), the subjects underwent a modified frequent sampling intravenous glucose tolerance test during which they remained in stalls and had access to grass hay and water ad libitum. Samples were colleted at -60, -45, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 35, 40, 50, 60 , 70 , 80, 90, 100, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min with a glucose bolus of 300 mg/kg BW at 0 min and an insulin bolus of 1.5 mU/kg BW at 20 min. Plasma was analyzed for glucose, insulin, growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations. Insulin sensitivity, glucose effectiveness, acute insulin response to glucose and disposition index were derived using Minmod Millennium and WinSAAM software. Diet groups were compared using the non-parametric Kruskal-Wallis test or the sign test. Time interactions were compared using a mixed model with repeated effects. Rank-ordered linear regression was used for correlations. Basal glucose did not differ between groups (P = 0.75). There was nearly a trend towards higher basal (P = 0.11), and median insulin was higher in the sugar and starch foals at all 36 sample points (P = 0.030). The basal glucose:basal insulin ratio for the sugar and starch supplemented foals was lower than for fat and fiber foals (P = 0.025). Insulin sensitivity (SI) was lower in foals fed sugar and starch than foals fed fat and fiber (P = 0.007). Acute insulin response to glucose was directly correlated to weight (r = 0.78; P = 0.003) and inversely correlated with SI (r = -0.55; P = 0.067). The glucose:insulin ratio was directly correlated to SI (r = 0.92; P < 0.001). Growth hormone concentrations were increased from basal from 19 to 180 min after the glucose dose (P < 0.05). Basal IGF-I was higher (P = 0.006) in the SS group compared to the FF group. Concentrations of total IGF-I increased with time (P = 0.002) in the SS group. The change in IGF-I concentration from baseline to the end of the study was positively correlated (r = 0.72; P = 0.008) to the area under the insulin curve from 0 to 80 min. Basal IGF-I was inversely correlated to SI (r = 0.71; P = 0.015). These results show that the metabolic response to a diet high in hydrolyzable carbohydrates differs from the response to a fat and fiber meal resembling forage. Weanlings adapted to meals high in glucose equivalents have higher insulin and IGF-I secretion as compared to foals adapted to a fat and fiber feed, possibly contributing to lower insulin sensitivity observed in these foals. Such deviations may contribute to metabolic dysfunction and osteochondrosis in horses fed grain diets.Master of Science
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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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Bagley, Christopher James. "Analogues of Insulin-Like Growth Factor-1 / Christopher James Bagley." Title page, table of contents and summary only, 1989. http://web4.library.adelaide.edu.au/theses/09PH/09phb146.pdf.
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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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Bastian, Susan Elaine Putnam. "Transcellular transport of insulin-like growth factor-1 (IGF-1)." Title page, contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phb3255.pdf.
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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.
Full textAbstract:
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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Goodfellow, Mark. "Type 1 insulin-like growth factor signalling in malignant melanoma." Thesis, University of Oxford, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599998.
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Novel therapeutic strategies are sorely required for malignant melanoma, which has been shown to overexpress the type 1 insulin-like growth factor receptor (IGFIR) compared benign naevi. The 10Ft R mediates many features of the malignant phenotype and is an attractive anti-cancer therapeutic target. Inoculation with lGFlR depleted tumour cells has been shown to upregulate MHC Class 1 expression and confer protection from tumour rechallenge in vivo. The initial aim of this project was to investigate effects of IGFlR depletion on MHC Class I expression and its functional significance in melanoma cells IGF 1 R gene silencing, but not IGFIR inhibition, caused a significant increase in surface MHC Class 1 expression in one murine cell line, B16.FIO, but 0/8 human melanoma cell lines. In B16.FI0 cells, increased MHC Class 1 did not affect cell lysis or cytokine production by, or proliferation of, activated T lymphocytes in vitro. These results indicate that the increase in MHC Class I in melanoma cells is not of functional significance. The main focus of this project then addressed a key issue relevant to clinical trials of IGF I R inhibition. Identifying features which render melanoma cells sensitive to IGF1R inhibitors is important to select patients suitable to receive this therapy. The approach was to define changes in gene expression after IGFl or IGflR inhibitor treatment of melanoma cells. Initial experiments were performed to select concentrations of IGF1 and IGFlR inhibitor AZ1225380 I, the latter based on GI50 concentrations. An IGF gene signature was created which was significantly correlated to Ki67 expression, a proliferation marker, in clinical datasets. This suggests a rationale for IGFlR targeting in clinical melanoma. Gene expression profiling identified that IGF and IGflR inhibition had reciprocal effects on expression of HBP1, a transcriptional repressor of prognostic significance in breast cancer. HBPl was validated as an IGFI regulated gene, and experiments using signalling inhibitors indicated that IGFlR regulates HBP I via the P13K pathway. HBPI depletion did not influence effects of IGF IR inhibition on proliferation. However HBP1 induction appeared to mediate effects of AZ12253801 on inhibiting the WNT pathway, measure1 by TOPIFOP reporters, and HBP l depletion enhanced basal and WNT-induced NMYC expression. NMYC has not previously been reported to be a Wnt/β catenin target gene in neoplastic cells. These results encourage further investigation into the effects of IOF 1.K! In regulating HBPl, particularly with respect to dual lGFlR Wnt/β catenin targeting
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Wilson, Helen Elizabeth. "Expression of insulin-like growth factor-I in ovine liver." Thesis, University of Reading, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384908.
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Kawamoto, Kazuyuki. "Role of Insulin-like growth factor-2 in colorectal cancer." Kyoto University, 1998. http://hdl.handle.net/2433/156995.
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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものであるKyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第7548号
医博第2058号
新制||医||702(附属図書館)
UT51-99-A234
京都大学大学院医学研究科分子医学系専攻
(主査)教授 下遠野 邦忠, 教授 日合 弘, 教授 今村 正之
学位規則第4条第1項該当
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Yoon, Diana Meeae. "Insulin-like growth factor-1 signaling in engineered articular cartilage." College Park, Md.: University of Maryland, 2008. http://hdl.handle.net/1903/8902.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2008.Thesis research directed by: Dept. of Chemical Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Yasa, Joe. "Insulin-like Growth Factor-1 in post-pneumonectomy lung regeneration." Thesis, Yasa, Joe (2019) Insulin-like Growth Factor-1 in post-pneumonectomy lung regeneration. PhD thesis, Murdoch University, 2019. https://researchrepository.murdoch.edu.au/id/eprint/50128/.
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Insulin Growth Factor-1 (IGF-1), is a key and highly regulated molecule which stimulates somatic growth. The level of serum IGF-1 in humans peaks at adolescence and declines with age. IGF-1 expression is also critical for embryonic lung development and is expressed in the regenerating lung of young animals following pneumonectomy (PNX), the surgical removal of a lung. The murine left-lung PNX model was used to investigate the hypothesis that IGF-1 enhances the regenerative capacity of the lung. The potential interactions of IGF-1 and the transcription factors early growth response protein 1 (EGR-1) and hypoxia-inducible factor-1α (HIF-1α) in post-PNX lung growth was also investigated.
I demonstrated that following left-lung PNX in young mice (aged 2-3 months) pre-operative total lung volume and tissue volume is restored by day 21 post-surgery. IGF-1 mRNA and protein levels were significantly induced in the remaining lung, with a transient but significant increase in IGF-1+, pIGF-1R+ and pERK-1/2+ lung cells, at day three post-PNX compared to SHAM treated mice. I then showed that intraperitoneal administration of IGF-1 following PNX significantly increases the rate of lung volume and tissue volume recovery and the level of lung cell proliferation, when assessed at day seven post-surgery. In contrast, blocking IGF-1 activity by pharmacological inhibition of IGF-1R signalling, significantly attenuated post-PNX lung growth.
In young mice receiving continuous subcutaneous infusion of IGF-1 following PNX, the rate of lung volume recovery to pre-operative levels was similar to age-matched PBS-treated PNX mice. However, lung sections assessed at day 23 post-surgery revealed that IGF-1-treated mice lungs had significantly higher numbers of IGF-1+, pIGF-1R+, pERK-1/2+ lung cells, proliferating SpC+ type two alveolar epithelial cells and number of alveoli per unit area, suggesting that IGF-1 treatment was associated with additional regenerative activity.
In old PNX mice (aged 22-24 months), there was a significant increase in aerated lung volume following continuous subcutaneous administration of IGF-1, compared to age-matched PBS-treated controls. However, unlike young mice, there was no evidence of restoration of pre-operative total lung volume or tissue volume by day 21 post-surgery in either treatment groups. Additionally, lung sections assessed at day 23 post-surgery revealed no differences between IGF-1 and PBS treated lungs in the numbers of IGF-1+, pIGF-1R+ and pERK-1/2+ lung cells, or proliferating SpC+ alveolar type two epithelial cells or the number of alveoli per unit area.
Finally, I investigated the potential for interactions of IGF-1 and the transcription factors EGR-1 and HIF-1α in post-PNX lung growth. I demonstrated that IGF-1 treatment can induce EGR-1 and HIF-1α protein expression in cultured 3T3 fibroblasts. Furthermore, both EGR-1 and HIF-1α were transiently increased in the parenchyma of the lung at day three post-PNX, coinciding with the peak of IGF-1 expression. Pharmacological inhibition of either EGR-1 or HIF-1α activity significantly reduced the density of CD31+ cells and CD31 protein levels in the lung. Additionally, pharmacological inhibition of HIF-1α activity in the lung following PNX significantly reduced lung cell proliferation at day seven post-surgery. Intraperitoneal administration of IGF-1 was able to restore the level of lung cell proliferation in HIF-1α inhibited PNX lungs to the levels of untreated PNX lungs.
These results collectively point to a temporally coordinated involvement IGF-1, EGR-1 and HIF-1α during post-PNX regenerative lung growth, and that additional IGF-1 treatment can enhance such growth following PNX in young mice, but not in aged mice. Furthermore, these studies have identified a potential age-dependent defect in responsiveness to IGF-1 in the lung, which warrants further investigation.
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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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Craven, Cyril John. "The mechanism of maturation of insulin-like growth factor-1." Thesis, Queensland University of Technology, 1999. https://eprints.qut.edu.au/37030/7/37030_Digitised%20Thesis.pdf.
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This study, to elucidate the role of des(1-3)IGF-I in the maturation of IGF-I,used two strategies. The first was to detect the presence of enzymes in tissues, which
would act on IGF-I to produce des(1-3)IGF-I, and the second was to detect the potential products of such enzymic activity, namely Gly-Pro-Glu(GPE), Gly-Pro(GP) and des(l-
3)IGF-I. No neutral tripeptidyl peptidase (TPP II), which would release the tripeptide GPE from IGF-I, was detected in brain, urine nor in red or white blood cells. The TPPlike
activity which was detected, was attributed to a combined action of a dipeptidyl peptidase (DPP N) and an aminopeptidase (AP A). A true TPP II was, however,
detected in platelets. Two purified TPP II enzymes were investigated but they did not release GPE from IGF-I under a variety of conditions. Consequently, TPP II seemed
unlikely to participate in the formation of des(1-3)IGF-I.
In contrast, an acidic tripeptidyl peptidase activity (TPP I) was detected in brain and colostrum, the former with a pH optimum of 4.5 and the latter 3.8. It seems likely
that such an enzyme would participate in the formation of des( 1-3 )IGF-I in these tissues in vitro, ie. that des(1-3)IGF-I may have been produced as an artifact in the isolation of IGF-I from brain and colostrum in acidic conditions. This contrasts with suggestions of
an in vivo role for des(1-3)IGF-I, as reported by others.
The activity of a dipeptidyl peptidase N (DPP N) from urine, which should release the dipeptide GP from IGF-I, was assessed under a variety of conditions and with
a variety of additives and potential enzyme stimulants, but there was no release of GP. The DPP N also exhibited a transferase activity with synthetic substrates in the
presence of dipeptides, at lower concentrations than previously reported for other acceptors or other proteolytic enzymes. In addition, a low concentration of a product,possibly the tetrapeptide Gly-Pro-Gly-Leu, was detected with the action of the enzyme on IGF-I in the presence of the dipeptide Gly-Leu.
As part of attempts to detect tissue production of des(1-3)IGF-I, a monoclonal antibody (MAb ), directed towards the GPE- end ofiGF-I was produced by immunisation
with a 10-mer covalently attached to a carrier protein. By the use of indirect ELISA and inhibitor studies, the MAb was shown to selectively recognise peptides with anNterminal
GPE- sequence, and applied to the indirect detection of des(1-3)IGF-I.
The concentration of GPE in brain, measured by mass spectrometry ( MS), was low, and the concentration of total IGF-I (measured by ELISA with a commercial
polyclonal antibody [P Ab]) was 40 times higher at 50 nmol/kg. This also, was not consistent with the action of a tripeptidyl peptidase in brain that converted all IGF-I to
des(1-3)IGF-I plus GPE. Contrasting ELISA results, using the MAb prepared in this study, suggest an even higher concentration of intact IGF-I of 150 nmollkg. This would
argue against the presence of any des( 1-3 )IGF-I in brain, but in turn, this indicates either the presence of other substances containing a GPE amino-terminus or other cross reacting epitope. Although the results of the specificity studies reported in Chapter 5 would make this latter possibility seem unlikely, it cannot be completely excluded. No GP was detected in brain by MS.
No GPE was detected in colostrum by capillary electrophoresis (CE) but the interference from extraneous substances reduced the detectability of GPE by CE and this
approach would require further, prior, purification and concentration steps. A molecule, with a migration time equal to that of the peptide GP, was detected in colostrum by CE, but the concentration (~ 10 11mo/L) was much higher than the IGF-I concentration measured by radio-immunoassay using a PAb (80 nmol/L) or using a Mab (300-400 nmolL). A DPP IV enzyme was detected in colostrum and this could account for the GP, derived from substrates other than IGF-1. Based on the differential results of the two antibody assays, there was no indication of the presence of des(1-3)IGF-I in brain or colostrum.
In the absence of any enzyme activity directed towards the amino terminus of IGF-I and the absence any potential products, IGF-I, therefore, does not appear to
"mature" via des(1-3)IGF-I in the brain, nor in the neutral colostrum. In spite of these results which indicate the absence of an enzymic attack on IGF-I and the absence of the expected products in tissues, the possibility that the conversion of IGF-I may occur in neutral conditions in limited amounts, cannot be ruled out. It remains possible that in the extracellular environment of the membrane, a complex interaction of IGF-I, binding protein, aminopeptidase(s) and receptor, produces des(1-
3)IGF-I as a transient product which is bound to the receptor and internalised.
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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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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/.
Full textAbstract:
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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Hedman, Christina A. "Insulin and IGF-I in type 1 diabetes /." Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med915s.pdf.
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Kallincos, Nicholas Campbell. "Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in vivo: investigation via transgenesis in rats." Thesis, Adelaide, 1993. http://hdl.handle.net/2440/21602.
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