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Matz-Soja, Madlen, and Rolf Gebhardt. "Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levels." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142560.
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Background
Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial.
Findings
Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels.
Conclusions
Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.
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Green, Charmaine. "THE ROLE OF INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR SIGNALLING IN THE MOUSE EMBRYO DURING PREIMPLANTATION DEVELOPMENT AND EARLY IMPLANTATION." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/17684.
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The use of assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) is increasing and today close to 4 percent of babies born in Australia, are as a result of ART. IVF procedures involve the culture of resultant embryos in medium that routinely lacks the growth factors that are present in the reproductive tract. Cultured embryos develop at a slower rate and have higher levels of developmental arrest, with fewer than 50% of embryos reaching the blastocyst stage. Furthermore, once an embryo is transferred back into the uterus, it faces the hurdle of implantation, with implantation failure being a major cause of IVF failure. This thesis examines whether the addition of growth factors to the embryo culture medium can increase blastocyst development and adhesion competency, using mouse embryos as a model system. In particular, the effect of insulin-like growth factor 1(IGF1) and insulin-like binding protein 3 (IGFBP3) on preimplantation mouse embryo development in vitro and the role of IGF1 on implantation in vitro was examined. In the present study, the culture of preimplantation embryos in the presence of a physiological concentration of IGF1 improved development from compaction onwards, resulting in improved blastocyst development. Conversely, high levels of IGF1 negatively impacted on development by decreasing hatching probably due to these high levels of IGF1 causing IGF1 receptor (IGF1R) down-regulation and apoptosis in the mouse embryo, as shown previously. Blocking the IGF1R with a neutralising antibody was shown to decrease blastocyst development, hatching and cell numbers and to increase apoptosis. Furthermore, treatment of blastocysts with IGF1 caused phosphorylation of Akt, which regulates cell survival by activating anti-apoptotic pathways. Therefore, IGF1 may act as a survival factor in the preimplantation embryo. During early implantation integrins accumulate on the surface of the blastocyst and endometrium and these interact with each other via extracellular matrix proteins such as fibronectin. These interactions are important for the attachment of blastocysts to the endometrium. In the present study treatment of blastocysts with IGF1 increased fibronectin on the surface of the blastocyst via activation of the Phosphoinositide 3 Kinase (PI3K) pathway. As a result, blastocysts had increased attachment to cultured uterine epithelial cells and increased outgrowth. In addition to IGF1, the reproductive tract produces IGFBP3, which is also thought to improve development of the embryo. However, to the best of our knowledge this is the first study to examine the effect of exogenous IGFBP3 on embryo development in vitro. IGFBP3 caused an increase rate of progression of embryos through the early stages of division (5-8cells) and activation of Akt and ribosomal protein S6 (rpS6) proteins as well as induction of calcium signalling. In the present study, it appears that IGFBP3 signalling in the embryo requires the IGF1R, as the use of an IGF1R neutralising antibody blocked IGFBP3 from enhancing early stages of division and the induction of calcium signalling. In other cell types, IGFBP3 signals through the IGF1R following a transactivation event involving the Sphingosine 1-Phosphate (S1P) pathway. The complex interactions and signalling of IGFBP3 are beginning to emerge in a number of different cell types and further investigation of IGFBP3 function is required in the embryo. As growth factors are generally absent from embryo culture media there is a potential avenue for the improvement of embryo culture and ART outcomes by addition of IGF1 and or IGFBP3 to the culture medium. The requirements of the embryo are complex and understanding the role of growth factors in embryo development is essential in order to optimise embryo culture and develop culture media for use in ART.
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Lin, Wan-Jung. "The nuclear actions of IGFBP-3." Online access for everyone, 2006. http://www.dissertations.wsu.edu/Thesis/Summer2006/w%5Flin%5F072606.pdf.
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Eddiry, Sanaa. "Rôle du SNORD116 et de l'IGFBP7 dans la réponse à l'IGF1 dans le syndrome de Prader-Willi." Toulouse 3, 2013. http://www.theses.fr/2013TOU30215.
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Le syndrome de Prader-Willi (SPW) est une maladie génétique complexe du développement qui résulte de l'absence d'expression de gènes sur le chromosome15q11-q13 paternel. Les patients SPW présentent des taux de GH diminués et des taux de ghréline élevés. Ils sont traités précocement par GH. La région du chromosome 15q11-q13 responsable du SPW est soumise au phénomène d'empreinte génétique, des études récentes la limitent à une région minimale incluant un cluster de small nucleolar RNA (snoARN): le SNORD116. Nos résultats montrent une sensibilité accrue à l'IGF1 et à l'insuline dans les fibroblastes de patients SPW. Ces cellules montrent également un taux augmenté de la prolifération et une diminution de la sénescence. Des études par microarrays, RT-qPCR, ainsi que du sécrétome montrent que l'expression de l'IGFBP7, un important facteur anti-prolifératif, a été considérablement abaissée chez ces patients. IGFBP7 est connu pour interagir avec les récepteurs de l'IGF1 et de l'insuline en modulant négativement leur action. Ces résultats étaient identiques chez la patiente SD. Notre hypothèse a été que l'augmentation de la prolifération et de la sensibilité aux facteurs de croissance est due à l'absence de l'expression du SNORD116. Nous avons démontré que le défaut du SNORD116 entraîne des taux de prolifération élevés et une diminution de la sénescence chez les patients SPW, avec une diminution de la sécrétion de l'IGFBP7. Les taux d'IGFBP7 in vitro décroissent sous l'effet de l'IGF1. De plus nous avons constaté que l'augmentation des taux d'IGF1 était corrélée significativement avec la diminution des taux de l'IGFBP7 chez des enfants SPW traités par GH pendant un an. Ces études soulignent fortement l'importance du SNORD116 pour contrôler la production de l'IGFBP7 en présence d'IGF1 et de facteurs de croissance et donc la sensibilité au traitement à l'hormone de croissancePrader-willi syndrome (PWS) is a complex genetic disease of neurodevelopment that arises from lack of expression of paternally imprinted genes on chromosome 15q11-q13. GH levels are low in PWS, and GH treatment is recommended. The current management of PWS patients includes early treatment by growth hormone (GH). We demonstrated that GH treatment of PWS patients is associated with elevated IGF1 levels. Human chromosome 15q11-q13 contains an imprinting control region, which when deleted is sufficient to cause PWS. In addition, human genetic studies have defined a minimal PWS gene locus including a cluster of paternally expressed small nucleolar RNA (snoRNA), within the SNORD116. This makes PWS the first human disease found to be caused by loss of non-coding RNA. Our results showed increased sensitivity to IGF1 and Insulin in PWS cells. These cells demonstrate also increased proliferation rate and decreased senescence. From multi-array and RT-qPCR analysis, expression of IGFBP7, an important antiproliferative factor, was dramatically decreased in those patients. IGFBP7 is known to interact with IGF1 and Insulin receptors to decrease their action. We demonstrated that the lack of expression of SNORD116 in this patient results in increased response to IGF1 and Insulin and highly decreased secretion of IGFBP7. Therefore lack of SNORD116 results in high proliferation rate and decreased senescence in PWS, with decreased IGFBP7 secretion. Finally, we found that the increase of IGF1 level was significantly correlated with the decrease of IGFBP7 level in the serum of PWS children treated one year with GH. These data suggest that the lack of SNORD116 expression results in increased responsiveness to growth factors due to a low level of IGFBP7 in cells of PWS patients. They highlight a new phenotype of PWS, modified IGFBP7 levels, which, given the properties of IGFBP7 as a strong regulator of IGF1 effect, has potential consequences on the management of PWS patients treated by GH
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Grosse, Christina Maria. "Knochenalterassozierte IGF-I und IGFBP-3 Befunde." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-93014.
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HO, Penny Pei-Ying. "NOVEL IGF-INDEPENDENT MECHANISMS OF IGFBP-5." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/10010.
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Insulin-like growth factor binding proteins (IGFBPs) are a group of six structurally similar proteins that modulates the mitogenic actions of IGFs through high binding affinity. IGFBP-5 and -3 has been reported to function independently of their IGF-binding ability and this involves interaction with several non-IGF proteins. Yeast two-hybrid and co immunoprecipitation (co-IP) assays identified SPRY2 and GADD34 as novel IGFBP-5-interacting partners. In MCF 10A cells, IGFBP 5:SPRY2 interaction potentiated SPRY2-mediated inhibition to EGF-stimulated DNA synthesis while IGFBP-5 expression alone had no effect. Under EGF-stimulation, cell numbers was decreased in SPRY2 and IGFBP 5 transfected cells to 24 % and 52 %, respectively, and a further reduction to 80 % was observed when cells co-expressed SPRY2 and IGFBP-5. These findings suggest a synergistic effect of the IGFBP-5:SPRY2 interaction. Biochemical analysis demonstrated that GADD34 binds to IGFBP 5 and -3, but not -1, -2, -4 and -6, and that amino acids between 320 and 400 were required for the interaction. Further co-IP showed that IGFBP-5 forms a complex with GADD34 and protein phosphate 1 alpha and in return, accelerate the survival of breast cancer MCF-7 cells from stress stimuli. In summary, we have characterised two novel mechanisms and expanded the current understanding of IGF-independent functions of IGFBP-5.
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TROTTA, ROSA. "A novel biomarker for cancer and autoimmune diseases: IGFBP6." Doctoral thesis, Università degli Studi di Foggia, 2019. http://hdl.handle.net/11369/382356.
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La temperatura corporea costituisce un importante meccanismo di difesa ed è il risultato di una complessa interazione che coinvolge numerosi fattori. Nell'uomo sano, la temperatura corporea è finemente regolata; deviazioni di 0.5°C oltre il limite superiore possono indicare una condizione patologica. Numerosi agenti possono indurre ipertermia, tra cui, insufficienza cardiaca acuta/cardiomiopatia acuta da stress [1] e infarto miocardico acuto [2] sindrome neurolettica maligna [3], endocrinopatie [4, 5], disturbi del sistema nervoso centrale (SNC) [6] e patologie oncologiche [7]. Le temperature febbrili aumentano l'efficacia della risposta immunitaria durante le infezioni stimolando il sistema immunitario innato e adattativo. Questo studio ha come obiettivo quello di dimostrare come l'ipertermia possa indurre modifiche del profilo di espressione genica e di evidenziare nuovi marker precoci di prognosi/diagnosi in patologie autoimmuni e/o tumorali. Nelle cellule dendritiche, alcuni tra i geni up-regolati codificano per proteine secrete, come IGFBP6 [8]. In condizioni ipertermiche, questa proteina induce chemiotassi dei monociti, dei linfociti T, ma non dei linfociti B. Inoltre, IGFBP6 è un agonista selettivo nei neutrofili poiché aumenta sia il burst ossidativo che la degranulazione e agisce come fattore chemotattico.Body temperature is an important defense mechanism and is the result of a complex interaction of many factors. In healthy human, the body temperature is regulated very carefully; deviations of 0.5°C above the upper limit of normal are considered to be significant indications of disease. Numerous elements may induce febrile conditions, including acute heart failure/stress cardiomyopathy [1] and acute myocardial infarction [2] neuroleptic malignant syndrome [3], endocrinopathies [4, 5], central nervous system (CNS) disorders [6] and oncological diseases [7]. Febrile temperatures increase the effectiveness of the immune response during infections by stimulating both the innate and adaptive arms of the immune system. The aim of this study is to demonstrate how hyperthermia can induce changes in the gene expression profile and highlight new early markers of prognosis/diagnosis in autoimmune and/or tumor pathologies. Among the up-regulated genes in dendritic cells, some encode secreted proteins, such as IGFBP6 [8]. This protein may have a functional role in the hyperthermic conditions as chemoattractant factor in monocytes and T cells, but not in B cells. Moreover, IGFBP6 is a selective neutrophil agonist, increasing oxidative burst and degranulation, as well as functioning as a chemotactic factor.
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Pillai, Chitra Claire. "IGFPBp1 : a multifunctional role in implantation, embryonic and fetal development." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271064.
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Paula, Mariana Teresa Alves Sarti de. "Estudo da expressão do IGF1R mRNA em meninas com puberdade precoce central antes e durante o tratamento com análogos do GnRH." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17144/tde-20072016-142344/.
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INTRODUÇÃO Na puberdade, tanto fisiológica quanto precoce, um dos eventos marcantes é o estirão de crescimento. Análogos do GnRH tem sido utilizado como tratamento da puberdade precoce central (PPC) tendo como consequência o bloqueio do eixo gonadal e diminuição da velocidade de crescimento, porém mantém níveis séricos elevados de IGF-I e IGFBP-3. Não existem relatos sobre a expressão do IGF1R durante a puberdade. Considerando-se que este poderia ser um ponto de regulação da velocidade de crescimento, o presente estudo propõe avaliar a expressão do IGF1R em meninas com PPC antes e durante o tratamento. MÉTODOS: Avaliamos meninas com PPC que foram divididas em dois grupos: Grupo A foi constituído por 16 meninas avaliadas antes do início do tratamento com idade média de 8,0+-0,7anos e o Grupo B constituído por 16 pacientes em uso regular do análogo do GnRH com idade média de 9,4+-0,8 anos. O grupo controle foi composto por 18 crianças saudáveis, pré-púberes com idade média 7,1+-1,3 anos. RESULTADOS: A expressão do mRNA do gene do IGF1R foi maior no grupo B quando comparado ao grupo A (p= 0,04) e ao grupo controle (p=0,004). Não foi observado diferença estatística entre o Grupo A e o grupo controle (p=0,17). Os níveis séricos de IGF-I e IGFBP3 assim como a relação molar IGF-I/IGFBP3 foram significativamente maiores no grupo A em relação ao grupo controle. (p<0,0001). Não encontramos diferença nas concentrações de IGF-I, IGFBP3 ou na relação molar entre os grupos A e B. O grupo controle apresentou níveis mais elevados de IGFBP1 quando comparado com os grupos A e B (p<0,001). Ao compararmos somente os grupos A e B, o grupo B apresentou número estatisticamente maior de valores indetectáveis de IGFBP1 quando comparado com o grupo A (p=0,01) mostrando uma tendência a valores menores no grupo B. A dosagem de insulina foi significativamente menor no grupo controle quando comparado ao grupo A (p<0,001) e não apresentou diferença entre os grupos A e B. Ao analisarmos os 3 grupos (controle, A e B) não encontramos a correlação negativa entre insulina e IGFBP-1. Essa correlação aparece quando avaliamos somente o grupo controle e o grupo A (r= - 0,5; p=0,007) e desaparece quando acrescentamos o grupo B na análise. CONCLUSÃO: As variações nas concentrações séricas de IGF-I, IGFBP-3, IGFBP-1 e insulina não explicam a desaceleração da velocidade de crescimento durante o tratamento de meninas com puberdade precoce central com análogos do GnRH. O aumento da expressão do IGF1R parece refletir uma redução da sinalização intracelular do IGF1R com consequente diminuição da bioatividade do IGF-I em um mecanismo de feedback de alça ultra curta. O aumento da secreção do hormônio de crescimento devido a redução do feedback negativo na hipófise, explica as concentrações encontradas de IGF-I, IGFBP3 e IGFBP1.Estudos outros serão necessários para confirmar esta hipótese, avaliando diferentes pontos de sinalização na cascata pós-receptorBACKGROUND: Growth spurt is a major event in central precocious puberty (CPP). GnRH analogues (GnRHa) treatment inhibit gonadal axis and decrease height velocity. However, serum IGF-I and IGFBP-3 remain high as before treatment. No reports regarding IGF type 1 receptor (IGF1R) in CPP is available. Considering that this could be a point of regulation of height velocity, the present study aims to study IGF1R mRNA expression in girls with CPP before and during GnRHa treatment. MÉTHODS: Sixteen girls with CPP (8.0±0.7yr) were evaluated before treatment (Group A) and sixteen (9.4±0.8yr) in use of GnRHa (Group B). Age-matched pre pubertal children were studied as controls (n=18). Fasting blood sample were collect for IGF1R mRNA expression analysis in peripheral lymphocytes (RT-PCR) and serum IGF-I, IGFBP-3, IGFBP-1 and insulin determination. RESULTS: The expression of IGF1R mRNA was higher in Group B than in Group A (p=0.04) and Controls (p=0.004). No difference was observed between Groups A and Controls. IGF-I, IGFBP-3 and IGF-I/IGFBP3 molar ratio were similar in Group A and B but higher than in Controls (p<0.0001). IGFBP-1 was higher (p<0.0001) in Controls than in Groups A and B. When we compare only Groups A and B, group B showed more IGFBP1 undetectable values than group A (p = 0.01) showing a tendency to lower values in group B. Insulin levels were lower in Controls than in Group A (p<0.001), but no difference were observed between Groups B and A. Negative correlation was found between insulin and IGFBP-1 when controls and Group A were put together (r= -0.5; p=0.007). This correlation disappear if Group B is included in the analysis. CONCLUSION: Serum concentrations of IGF-I, IGFBP-3, IGFBP-1 and insulin do not explain the decrease in height velocity during CPP treatment with GnRH analogue. The increase in IGF1R mRNA expression suggest impairment of IGF-I signaling and compensatory up regulation of the IGF1R. Increased GH concentrations due to reduction of IGF-I feedback could explain the IGF-I, IGFBP-3 and IGFBP-1 findings. Other studies are necessary to confirm this hypothesis by studying different signaling points in post-receptor cascade
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Wilhelm, Franziska Katharina. "Der PI3K/AKT/mTOR-Signalweg und die Produktion des Insulinähnlichen Wachstumsfaktorbindungsproteins-2 (IGFBP-2) in humanen Adipozyten." Doctoral thesis, Universitätsbibliothek Leipzig, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-219991.
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In den letzten Jahren wurde gezeigt, dass die Serumkonzentration des insulinähnlichen Wachstumsfaktorbindungsproteins-2 (IGFBP-2) bei Krebserkrankungen, die mit dem Verlust des Tumorsuppressorgens PTEN einhergehen, erhöht ist und daher möglicherweise einen Marker für den PTEN-Status und die Aktivität des PI3K/AKT/mTOR-Signalweges darstellt. Schmid et al. haben 2014 einen Patienten mit PTEN-Hamartom-Tumor-Syndrom (PHTS) mit einer heterozygoten PTEN-Keimbahndeletion und massiver Lipomatose beschrieben, bei dem erhöhte IGFBP-2 Serumspiegel gemessen wurden. Ziel dieser Arbeit war es zu analysieren, ob PTEN-defiziente Lipomzellen des Patienten im Vergleich zu Kontrollfettzellen mehr IGFBP-2 produzieren, sowie den Einfluss verschiedener pharmakologischer Inhibitoren des AKT/PI3K/mTOR - und des MAPK- Signalwegs auf die IGFBP-2 Produktion zu untersuchen. In der PTEN-defizienten Lipomzellkultur, gewonnen aus reseziertem Lipomgewebe des Patienten, wurden vergleichbare Mengen an IGFBP-2 wie in den nicht PTEN-defizienten Kontrollzellen gefunden. Die pharmakologische Hemmung der PI3K und AKT bewirkten eine signifikante Senkung der IGFBP-2 Expression und Sekretion, wohingegen sich bei Hemmung der MEK und des mTORC1 keine Effekte zeigten. Diese Ergebnisse weisen darauf hin, dass eine heterozygote PTEN-Deletion in Lipomzellen nicht zu einer erhöhten IGFBP-2 Produktion führt und daher die erhöhten Serumspiegel des Patienten nicht darauf zurückzuführen sind. Des Weiteren bestätigen die in vitro Ergebnisse die klinische Beobachtung, dass unter der Therapie mit dem mTORC1-Inhibitor Rapamycin die IGFBP-2 Serumspiegel des Patienten nicht zurückgingen. Möglicherweise stellt IGFBP-2 jedoch einen geeigneten Verlaufsmarker für eine Therapie mit PI3K- oder AKT-Inhibitoren dar.
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Gschwind, Dana [Verfasser], and Martina [Akademischer Betreuer] Müller-Schilling. "Identifizierung von IGFBP-2 und IGFBP-4 als neue prognostisch relevante Zielgene der P53-Familie im hepatozellulären Karzinom / Dana Gschwind ; Betreuer: Martina Müller-Schilling." Regensburg : Universitätsbibliothek Regensburg, 2021. http://d-nb.info/124090178X/34.
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Schmidt, Susanne Eva Maria. "Funktionale Wachstumsanalyse der Nebennieren IGFBP-2- und GH-transgener Mäuse." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-42603.
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Breitsameter, Hannelore. "Holistische Proteomanalyse der Nebennieren bGH und IGFBP-2 transgener Mäuse." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-83946.
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Breitsameter, Hannelore. "Holistische Proteomanalyse der Nebennieren bGH und IGFBP-2 transgener Mäuse." kostenfrei, 2007. http://edoc.ub.uni-muenchen.de/8394/.
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Parghi, Nirav. "Characterization of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) interaction with the Bovine Aortic Endothelial (BAE) cell surface: Examination of the Role of Heparan Sulfate Proteoglycans (HSPG)." Thesis, Virginia Tech, 1998. http://hdl.handle.net/10919/36928.
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Insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the insulin-like growth factor (IGF-I). However, their precise role is as yet unclear. Further, recent studies have indicated that IGFBP-3 has a receptor mediated growth inhibitory response of its own. In the present study, we quantified the binding characteristics of IGFBP-3 to bovine aortic endothelial (BAE) cells. Binding studies at 4 oC were conducted and a specific binding curve for IGFBP-3 was obtained. IGFBP-3 was found to bind with an equilibrium dissociation constant (KD) value of 3.1 x 10-10 M. The role of heparan sulfate proteoglycans (HSPG) in the IGFBP-3 binding mechanism was also examined. It was seen that inactivation of the cell surface HSPGs with 75 mM sodium chlorate did not affect IGFBP-3 binding. Further, there have been reports of inhibition of IGFBP-3 binding by heparin in the media. Hence, the most probable interaction of HSPG with IGFBP-3 occurs in the extracellular region, with soluble HSPGs acting as receptors for IGFBP-3 and decreasing the net cell associated ligand receptor interaction. This is likely, since IGFBP-3 is known to possess a heparin binding domain. Simultaneous introduction of IGF-I and IGFBP-3 into the extracellular media decreased IGFBP-3 binding to the cell surface, which might imply that IGF-I and IGFBP-3 regulate each other's action.Master of Science
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Rolnik, Daniel Lorber. "Avaliação sequencial do colo uterino e do teste para proteína-1 fosforilada ligada ao fator de crescimento insulina -símile na predição do parto prematuro." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-22012014-112900/.
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INTRODUÇÃO: O antecedente de parto prematuro espontâneo em gestação anterior é considerado o principal e mais importante fator de risco clínico para prematuridade, principal causa de morbidade e mortalidade neonatal. Cerca de 25% das pacientes que tiveram parto prematuro apresentarão recorrência. A prevenção secundária consiste na pesquisa de marcadores de maior risco, com o intuito de instituir medidas terapêuticas apropriadas e de evitar tratamentos desnecessários. A hipótese do presente estudo é a de que existe correlação entre os resultados da avaliação do colo uterino e do teste para proteína-1 fosforilada ligada ao fator de crescimento insulina-símile (phIGFBP-1) e que a utilização de ambos em associação possa predizer a ocorrência de parto prematuro com maior sensibilidade. OBJETIVOS: Averiguar a utilidade da medida do comprimento do colo uterino e do teste para phIGFBP-1 na predição do parto prematuro antes de 37 e de 34 semanas, a existência de relação dos testes entre si, o melhor valor de corte da medida do colo em diferentes idades gestacionais e a melhor época de realização de cada um dos exames. MÉTODO: Foram compilados e submetidos a análise secundária os dados de 101 gestantes com antecedente de parto prematuro atendidas no Setor de Baixo Peso Fetal da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, entre 2003 e 2008. A medida do comprimento cervical e o teste para phIGFBP-1 foram realizados a cada três semanas, entre 24 e 34 semanas de gestação, e comparados com o desfecho de parto prematuro e nascimento com 34 semanas ou menos, e o melhor valor de corte do colo uterino foi estabelecido por meio de curva de características operacionais. RESULTADOS: Das 101 gestações estudadas, 25 (24,8%) terminaram em parto prematuro, das quais 12 (11,9%) ocorreram com 34 semanas ou menos. As idades gestacionais médias de avaliação foram de 24, 27, 30 e 33 semanas, e os valores de corte do colo uterino foram de 22, 21, 20 e 16 mm, respectivamente. A medida do comprimento do colo apresentou maior sensibilidade (cerca de 70%) e foi capaz de predizer o parto prematuro em todas as avaliações. O teste para phIGFBP-1 não foi útil com 24 semanas, porém foi capaz de detectar de forma independente o risco de prematuridade com 27, com 30 e com 33 semanas. Houve associação estatística dos exames entre si, de forma que o comprimento cervical médio foi menor em gestantes com teste positivo para phIGFBP-1. A associação dos exames elevou a sensibilidade e o valor preditivo negativo de forma significativa. CONCLUSÕES: A medida do comprimento do colo pela ultrassonografia transvaginal constitui bom marcador de risco para parto prematuro com 24 semanas, e o teste para phIGFBP-1 é útil após 27 semanas. A associação dos dois exames possui alta sensibilidade e alto valor preditivo negativo em gestantes de alto risco para prematuridade espontânea, e a realização do primeiro com 24 semanas e do segundo com 27 semanas constitui bom modelo preditivo para o parto prematuroINTRODUCTION: The history of spontaneous preterm birth in a previous pregnancy is considered the main and most important clinical risk factor for preterm birth, the leading cause of neonatal morbidity and mortality. About 25% of these patients will deliver prematurely again. Secondary prevention consists in the search for markers of increased risk, in order to institute appropriate therapeutic actions and to avoid unnecessary treatments. The hypothesis of this study is that there is a correlation between the results of the evaluation of the cervix and the test for phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and that the use of both in combination can predict the occurrence of preterm delivery with higher sensitivity. OBJECTIVES: To investigate the usefulness of the measurement of the cervical length and phIGFBP-1 rapid test in the prediction of preterm birth before 37 and 34 weeks, the existence of a relationship between the tests themselves, the best cutoff value of cervical length measurement at different gestational ages and the best time to carry out each of the exams. METHODS: Data of 101 women with previous preterm birth assisted at the Obstetrical Clinic of the Hospital das Clínicas, Faculty of Medicine, University of São Paulo between 2003 and 2008 were collected and subjected to secondary analysis. The measurement of cervical length and the phIGFBP-1 test were performed every three weeks, between 24 and 34 weeks gestation, and compared with the outcome of premature birth before 37 and 34 weeks, and the best cutoff value of the cervix was determined by receiver operator characteristic curves. RESULTS: Of the 101 pregnancies studied, 25 (24.8%) ended in preterm birth, of which 12 (11.9%) occurred at 34 weeks or less. The mean gestational age in each evaluation was 24, 27, 30 and 33 weeks, and the cutoff of the cervix were 22, 21, 20 and 16 millimeters, respectively. The measurement of cervical length showed the highest sensitivity (approximately 70%) and was able to predict preterm birth in all evaluations. The phIGFBP-1 test was not useful at 24 weeks, but was able to independently detect the risk of prematurity at 27, 30 and 33 weeks. Statistical association between the exams was observed, so that the mean cervical length was lower in pregnant women testing positive for phIGFBP-1. The combination of both tests significantly increased the sensitivity and negative predictive value. CONCLUSIONS: The measurement of cervical length by transvaginal ultrasound is a good marker of risk for preterm delivery at 24 weeks, and the test for phIGFBP-1 is useful after 27 weeks. The association of the two tests is valuable and shows high sensitivity and high negative predictive value in women at high risk for spontaneous preterm birth, when the first is preformed with 24 weeks, and the second with 27 weeks
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Šunić, Damir. "The role of IGFBPs in the regulation of chondrocyte metabolism in vitro /." Title page, contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phs9579.pdf.
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Laranjeira, Angelo Brunelli Albertoni 1981. "Participação do IGFBP7 na interação leucemia-estroma e na resistência a quimioterapia." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316896.
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Orientador: José Andrés YunesTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A Leucemia Linfóide Aguda (LLA) é o tipo de câncer mais comum que acomete crianças. Sabe-se que a interação do tumor com o contexto celular do hospedeiro (microambiente tumoral) é recíproca, ou seja, na medida em que o tumor estimula o seu microambiente, este potencializa a sobrevivência, proliferação e invasividade tumoral. A interação da LLA com as células estromais da medula óssea tem um impacto positivo na resistência das células leucêmicas à quimioterapia. No presente estudo foi investigado a modulação de uma série genes de sensibilidade e resistência à asparaginase em células de LLA-B precursoras após co-cultura com as células estromais. Mostramos o aumento da expressão e secreção da IGFBP7 pelas células leucêmicas após co-cultivo com células do estroma da medula óssea. Em ensaios com o silenciamento do IGFBP7 em células leucêmicas e células estromais, mostramos que a IGFBP7 atua regulando positivamente o crescimento celular e aumenta a resistência a asparaginase. A IGFBP7 'leucêmica' junto com IGF/insulina atua sobre as células estromais, induzindo nestas células o aumento da produção de asparagina, e diminuindo a ação da asparaginase. Além deste mecanismo de resistência dependente das células estromais, mostramos que a IGFBP7 em conjunto com IGF/insulina promove a resistência das células leucêmicas à ação de outros compostos quimioterápicos (dexametasona e metotrexato) de forma independente da interação leucemia-estroma. Ainda pode ser observado que o plasma de crianças com LLA ao diagnóstico, apresenta maiores níveis de IGFBP7 do que em amostras controles. É importante ressaltar que níveis mais altos de mRNA IGFBP7 foram associados com menor sobrevida livre de leucemia (Modelo de regressão de Cox, P = 0,003), em células de LLAB Ph(-) presursoras
Abstract: Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer that affects children. It is known that the interaction between tumor and the cellular context of the host (tumor microenvironment) is reciprocal, ie, to the extent that the tumor stimulates their microenvironment, this enhances the survival, proliferation and tumor invasiveness. The interaction of ALL with bone marrow stromal cells has a positive impact on leukemia resistance to chemotherapy. In the present study, we investigated the modulation of a series of putative asparaginase-resistance/sensitivity genes in B-precursor ALL upon co-culture with stromal cells. We showed an increase expression and secretion of IGFBP7 in leukemic cells after co-culture with BMSCs. Assays with IGFBP7 knockdown in leukemic cells and stromal cells, showed that IGFBP7 acts as a positive regulator of cell growth and increases resistance to asparaginase. 'Leukemic' IGFBP7 together with IGF/insulin acts on stromal cells, increasing asparagine production, thus reducing the asparaginase effect. Besides this mechanism of resistance dependent of stromal cells, we showed that IGFBP7 in conjunction with IGF/insulin promotes the resistance of leukemia cells to the action of other chemotherapeutic compounds (dexamethasone and methotrexate) independently of the interaction leukemia-stroma. We still observed that diagnostic BM plasma from children with ALL at diagnosis, have higher levels of IGFBP7 than control samples. Importantly, higher levels of IGFBP7 mRNA were associated with lower leukemia-free survival (Cox regression model, P = 0.003) in precursor B-ALL Ph (-) patients
Doutorado
Genetica Animal e Evolução
Doutor em Genetica e Biologia Molecular
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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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Lu, Xinping. "Identification of growth hormone response sequence in rat IGFBP-1 promoter." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq23394.pdf.
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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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Spanos, Jonathon L. "Characterisation of IGFBP-5 protease activity in Chinese hamster ovary cells /." Title page and contents only, 2002. http://web4.library.adelaide.edu.au/theses/09SB/09sbr729.pdf.
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Wallek, Grit [Verfasser]. "IGF-I und IGFBP-3 bei Patienten mit Lebererkrankungen / Grit Wallek." Greifswald : Universitätsbibliothek Greifswald, 2014. http://d-nb.info/1048162575/34.
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Haywood, Natalie Jayne. "Modulatory effects of IGFBP-1 on insulin sensitivity & glucose regulation." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/11519/.
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Obesity is a key factor in the development of insulin resistance. Insulin resistance plays a central role in the initiation and progression of type 2 diabetes mellitus and atherosclerosis. Developing novel therapeutic strategies to prevent and treat insulin resistance is therefore important. In humans, the circulating concentration of IGFBP-1 (Insulin like growth factor binding protein-1) has been proposed as a marker of insulin sensitivity. IGFBP-1 can impact on cellular functions via an RGD (α5β1 integrin binding) motif independent of IGF binding. However, whether IGFBP-1 is causally implicated in glucose regulation and could be exploited therapeutically, remained unexplored. In this series of studies, complementary in vitro and in vivo approaches were used to explore the effect and mechanism of IGFBP-1 on metabolic homeostasis. Metabolically relevant cell lines were used to investigate the effects of rIGFBP-1 and an RGD synthetic hexapeptide (which binds α5β1 integrin) on glucose uptake, the insulin signalling pathway and insulin secretion. Metabolic profiling of genetically modified mice over-expressing hIGFBP-1 was also performed. Finally, two different in vivo models of insulin resistance were used to investigate the potential of an RGD synthetic hexapeptide as a novel treatment for insulin resistance. Promisingly, in vitro, rIGFBP-1 increases glucose uptake and insulin sensitivity through integrin engagement and focal adhesion kinase activation. rIGFBP-1, through its RGD domain and integrin linked kinase also improves glucose-stimulated insulin secretion from pancreatic β-cells. Encouragingly, in vivo, both acute and chronic RGD treatments appear to improve glucose clearance and enhance insulin sensitivity. Therefore, the RGD domain of IGFBP-1 represents a promising potential new therapeutic target, that both enhances insulin sensitivity and insulin secretion, in the field of type 2 diabetes mellitus.
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Isotton, Ana Lúcia. "Efeitos do uso de estrógenos orais e transdêmicos sobre IGF-1, IGFBP-3, IGFBP-1, lipídios e metabolismo da glicose em pacientes com hipopituitarismo : um estudo ramdomizado." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2007. http://hdl.handle.net/10183/11362.
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O tratamento do hipogonadismo hipogonadotrófico na mulher adulta com hipopituitarismo inclui diversas alternativas terapêuticas de estrógenos e progestágenos, sendo a via oral a de menor custo e a de maior comodidade à paciente. A rota estrogênica oral, entretanto, exerce marcada influência sobre o eixo hormônio de crescimento/fator de crescimento insulinasímile número 1 (GH/IGF-1) nessas mulheres. O tratamento com estrógenos orais, concomitante ao uso de GH em pacientes com hipopituitarismo, antagoniza as ações biológicas do GH e agrava as anormalidades de composição corporal e o metabolismo em geral. Presume-se que o estrógeno oral iniba a secreção/produção de IGF-1 através de um efeito de primeira passagem hepática, causando um aumento da secreção de GH através de inibição do feedback negativo de IGF-1 em mulheres normais. Isso é demonstrado clinicamente por redução da massa magra, aumento da massa gorda, perfil lipídico aterogênico e prejuízo do bem-estar psicológico. Alguns estudos apontam que os progestágenos com ação androgênica revertem o efeito de diminuição dos níveis séricos de IGF-1 induzida pelos estrógenos orais. Progestágenos neutros não apresentam esse efeito, porém, quanto maior a potência androgênica, maior será a reversão do efeito de diminuição de IGF-1. Na presente revisão da literatura, serão abordados os aspectos clínicos da reposição com estrógenos e progestágenos nas mulheres com hipopituitarismo, suas interações nas outras deficiências hormonais, bem como o impacto do uso de estrógenos sobre as ações metabólicas do GH.Treatment of hypogonadotropic hypogonadism in adult woman with hypopituitarism can include a wide range of estrogen and progestogen treatment alternatives, and oral administration is the route of least cost and greatest patient comfort. The oral estrogen route has a major impact on the growth hormone-insulin-like growth factor I (GH-IGF-I) axis. Oral estrogen therapy, when given concurrently with GH to patients with hypopituitarism, antagonizes the biological effects of GH treatment and aggravates the abnormalities of body composition and the metabolism in general. It is presumed that oral estrogen suppresses the secretion/production of IGF-1 by a hepatic first-pass mechanism, resulting in increased GH secretion by means of suppressing the IGF-I negative feedback that is present in healthy women. This is manifest clinically in reduced lean body mass, increased fat mass, an atherogenic lipid profile and damage to psychological well-being. Some studies have indicated that progestogens with androgenic actions reverse the effect of reduced serum IGF-1 levels that is induced by the oral estrogens. Neutral progestogens do not exert this effect, however the stronger the androgenic potential, the more the effect of reduced IGF-1 will be reversed. This bibliographical review will deal with the clinical aspects of estrogen and progestogen replacement in women with hypopituitarism, their interactions with other hormone deficiencies and the impact of estrogen treatment on the metabolic actions of GH.
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Pires, Marcela de Oliveira. "Efeitos do treinamento físico sobre a cinética das concentrações séricas dos componentes do Complexo Ternário do IGF-I e citocinas (TNF-?, IL-6, IL-10) em nadadores adolescentes." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17144/tde-23042018-170959/.
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O eixo GH/IGF-I (hormônio do crescimento - fatores de crescimento insulina-símile) é um sistema de mediadores de crescimento, receptores e proteínas de ligação que controlam o crescimento somático e tecidual em muitas espécies e programas de exercícios estão relacionados a esta função anabólica por meio da ação deste eixo. Partindo deste pressuposto, o objetivo do presente estudo foi analisar a cinética das concentrações séricas de IGF-I, IGFBP-3 e ALS, das citocinas IL-6, IL-10 e TNF-? e comparar com o desempenho físico e a composição corporal de nadadores adolescentes nas diferentes fases de uma temporada de treinamento. A amostra foi composta por 9 nadadores adolescentes do sexo masculino com idade entre 16 e 19 anos, que faziam parte de uma equipe de natação universitária da cidade de Ribeirão Preto. Os níveis de IGF-I, IGFBP-3, ALS, IL-6, IL-10 e TNF-? foram determinados na fase básica, específica e final do polimento. A fim de comparar a cinética do sistema IGF-I/IGFBP-3-ALS e das citocinas com o desempenho físico e a composição corporal dos atletas, também foram avaliadas a resistência aeróbia em nado livre, a aptidão anaeróbia em nado atado, a massa corporal, o percentual de gordura e a massa magra nos diferentes momentos da temporada. Para a análise da cinética do sistema IGF-I/IGFBP-3-ALS e das citocinas nas diferentes fases do treinamento e antes e após a sessão de treino padronizada foram utilizados os testes não-paramétricos de Friedman e Wilcoxon, respectivamente, adotando-se um nível de significância de 0,05. A correlação entre duas variáveis foi analisada por meio do coeficiente de correlação de Spearman. Resultados: o IGF-I é sensível aos efeitos agudos e crônicos do treinamento, apresentando um comportamento em duas fases ao longo da temporada - uma fase catabólica (fase específica) e uma fase anabólica (polimento). O IGFBP-3 mostrou-se sensível apenas aos efeitos crônicos do treinamento, não sendo possível identificar um comportamento diferenciado intra-fase (pré x pós). A ALS manteve-se constante, mostrando que não foi afetada pelos efeitos agudos ou crônicos do treinamento. A IL-10 mostrou-se sensível aos efeitos agudos e crônicos do treinamento, aumentando significativamente durante a fase de polimento. A IL-6 não apresentou variação significante em resposta a uma sessão de treinamento (efeito agudo), apesar disso, apresentou uma correlação negativa com o IGF-I na fase específica de treinamento. O TNF-? apresentou concentrações mais estáveis ao longo da temporada. A composição corporal e a condição cardiorrespiratória dos nadadores não foram alteradas ao longo da temporada. O Pico de Força e a Força Média acompanharam a variação do IGF-I e do IGFBP-3, ou seja, diminuíram durante a fase específica e apresentaram uma elevação significativa durante o polimento. Conclusão: o IGF-I e a IGFBP-3 podem ser considerados um dos sensíveis marcadores de estado de treinamento, podendo orientar treinadores e atletas a dosar a intensidade de treinamento, especialmente de jovens que se encontram na puberdade. Foi possível observar algumas faces de interação com as citocinas, onde a soma das ações das citocinas provavelmente explicariam as mudanças nas concentrações séricas de IGF-I e IGFBP-3.The GH/IGF-I axis is a system of growth mediators, receptors, and binding proteins that regulate somatic and tissue growth; and it has been shown that exercise programs are related to the anabolic function of this axis. The aim of this study was to analyse the kinetics of serum IGF-I, IGFBP-3, ALS, IL-6, IL-10 and TNF-? concentration in adolescent swimmers at different stages of a training season, and compare them with physical performance parameters and body composition of the athletes. Nine male athletes, aged 16 to 19 years and who trained regularly throughout the season were included in this study. Serum IGF-I, IGFBP-3, ALS, IL- 6, IL-10, and TNF-? concentrations were recorded before and after (pre x post) standardized training sessions during the different stages of a training season (extensive x intensive x tapering). Aerobic endurance in freestyle, anaerobic fitness in tied swimming (Peak Force and Average Force), body mass, fat percentage, and lean body mass were also analysed at the different stages of training in order to compare the behaviour of the IGF-I/IGFBP/ALS system with the physical performance and body composition of the athletes. Variations in the cytokines and IGF-I/IGFBP-3/ALS system before and after a standardized training session, and at the different stages of training were analysed by the Wilcoxon and Friedman nonparametric tests, respectively. The correlation between the two variables was analysed by the Spearman\'s correlation coefficient. Significance was considered at P<0.05. Results: IGF-I was sensitive to the acute and chronic effects of training, exhibiting biphasic behaviour throughout the season. The catabolic phase was characterized by a reduction in serum IGF-I levels during the intensive stage while the anabolic phase was marked by an increase in posttraining serum IGF-I levels during the tapering stage. IGFBP-3 was only sensitive to the chronic effects of training, with a reduction in post-training serum levels during the intensive stage and an increase during the tapering stage. No difference was observed in pre- or posttraining IGFBP-3 levels at the different stages. ALS and TNF-? remained estable throughout the training season. IL-10 was sensitive to the acute and chronic effects of training, increasing significantly during the tapering phase. IL-6 showed no variation in response to a training session (acute effect); nevertheless, it had a negative correlation to IGF-I at the intensive phase. The body composition and cardiorespiratory function of the swimmers remained unaltered throughout the season. Peak Force and Average Force followed IGF-I and IGFBP-3 variations, with a decrease during the intensive stage and a significant increase during the tapering stage. The body composition and cardiorespiratory condition of the swimmers did not vary significantly throughout the season, exhibiting behaviour independent of IGF-I or IGFBP-3. Conclusion: Serum IGF-I and IGFPB-3 concentrations have proven to be sensitive markers of training status and, thus, may be used as guides for coaches and athletes in the challenging task of modulating training intensity in young athletes. The cytokine interactions observed suggest that the combined effects of these cytokines may be responsible for the serum IGF-I and IGFBP-3 variations recorded.
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Tao, Jia-Lin. "The Molecular Mechanisms Underlying Ligand Specificity of the Insulin and IGF-I Receptors." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278613018.
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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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Li, Zhuo. "Modulation of IGFBP2 upon aging, obesity and insulin resistance in mice and humans." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28371/28371.pdf.
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Burrows, Carla. "How do the IGFBPs elicit their IGF-independent actions in breast epithelial cells." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432729.
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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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Berg, Ulrika. "The IGF-IGFBP system in aerobic exercise - with focus on skeletal muscle /." Stockholm : Institutionen för kvinnors och barns hälsa, Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-379-5/.
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Pisa, Marcel Frezza. "Estudo dos possíveis efeitos do treinamento físico ao longo de uma temporada de treinamento sobre o eixo GH/IGF-I, proteínas de ligação dos IGFs em atletas de voleibol." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/109/109131/tde-04072018-092521/.
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Os hormônios de crescimento, principalmente os do eixo GH/IGF-I são responsáveis pelo crescimento tecidual e estrutural desde o nascimento. O GH produzido na hipófise é um hormônio com funções metabólicas e anabólicas e é o principal estimulador da síntese e liberação do IGF-I no fígado que tem suas ações endócrinas, parácrinas e autócrinas mediadas pelas IGFBPs. O exercício físico está intimamente ligado à função anabólica, estimulando a secreção e a ação dos hormônios do eixo GH/IGF-I.Existe a hipótese de haver um comportamento bifásico do eixo durante uma temporada de treinamento,caracterizado por uma fase catabólica, seguida de uma fase anabólica dependendo das fases do treinamento, porém vários estudos têm resultados controversos. O objetivo desse projeto foi investigar o impacto de uma temporada de treinamento em atletas de voleibol sobre o eixo GH/IGF-I e IGFBP-3 e sua relação com desempenho em testes físicos. A amostra foi composta por 10 jogadores de Voleibol categoria adulto da equipe de Franca-SP que foram analisados no início(A1), durante(A2) e ao final(A3) de 15 semanas de treinamento. Foram analisados dados antropométricos, altura de salto e potência de membros inferiores no Squat Jump (SJ), Counter Moviment Jump(CMJ)e Drop Jump 40 cm (DJ40), Índice de Força Reativa (IFR), Razão de Utilização Excêntrica (RUE) e concentrações deIGF-I e IGFBP-3. Para as análises estatísticas foram utilziadas ANOVA de medidas repetidas, Magnitude de Efeito (ES) e Probabilidade Quantitativa de Chances (QC). Os resultados mostram redução dos valores de Massa Coporal Total (MCT), Percentual de Gordura Coporal (%GC), Massa Magra (MM) e Massa Gorda (MG), com menor valor em A3, os resultados dos saltos apresentaram aumento linear com diferença estatísitca (p < 0,05) no DJ40 em A3. A sessão de treino não teve influência sobre as concentrações de IGF-I e IGFBP-3, indicando que a intensidade de disputa dessa modalide não é capaz de alterar as concentrações desses hormônios. Não foi verificada diferença estatísitca (p < 0,05) entre as coletas durante o período de treinamento, mas, as análises de ES e QC indicam tendência de aumento do IGF-I em A3. O comportamento bifásico do eixo GH/IGF-I não foi observado nesse estudo, possivelmente devido a forma de planejamento do período de treinamento, contudo, o IGF-I apresentou maiores concentrações em A3 coincidindo com os maiores resultados de altura de salto. Com esses resultados foi possível inferir que a concentração de IGF-I está correlacionada positivamente com o desempenho físico de atletas de voleibol e que a redução ou a incapacidade de aumento de IGF-I pode ser um sinal de alerta para atletas e treinadores. Ainda assim, são necessários novos estudos para investigar se o treinamento terá efeitos semelhantes durante longos períodos de treinamento, períodos de treinamento com maior intensidade, diferentes fases durante o período de preparação ou competição produzirão respostas hormonais semelhantesGrowth hormones, especially the GH/IGF-I axis is responsible for tissue and structural growth from birth. GH produced in the pituitary gland is a hormone with metabolic and anabolic functions and is the main stimulator for the synthesis and release of IGF-I in the liver that has its endocrine, paracrine and autocrine actions mediated by IGFBPs. Physical exercise is closely linked to anabolic function, stimulating the secretion and action of the hormones of the GH/IGF-I axis. There is a hypothesis of a biphasic behavior of the axis during a training season, characterized by a catabolic phase, followed by an anabolic phase depending on the training phases, but several studies have controversial results. The objective of this project was to investigate the impact of a training season on volleyball athletes on the GH/IGF-I axis and IGFBP-3 and its relation to performance in physical tests. The sample consisted of 10 adult category Volleyball players from the Franca-SP team who were analyzed at baseline (A1), during (A2) and at the end (A3) of 15 weeks of training. Anthropometric data, jump height and power of lower body in Squat Jump (SJ), Counter Movement Jump (CMJ) e Drop Jump 40 cm (DJ40), Reactive Force Index (RFI), Eccentric Usability Ratio (EUR) and IGF-I and IGFBP-3 concentrations were analyzed. Statistical analyzes were performed using repeated measures ANOVA, Effect Size test (ES) and Probability of Quantitative Chances(QC). The results show a reduction in Total Body Mass (TBM) values, Percentage of Body Fat (%BF), Lean Mass (LM) and Fat Mass (FM), with a lower value in A3, the jump results showed a linear increase with a statistical difference (p <0.05) in DJ40 in A3. The training session had no influence on the concentrations of IGF-I and IGFBP-3, indicating that the intensity of contention of this modality is not able to alter the concentrations of these hormones. There was no statistically significant difference (p <0.05) between the collections during the training period, but the ES and QC analyzes indicated an upward trend in IGF-I in A3. The biphasic behavior of the GH/IGF-I axis was not observed in this study, possibly due to the planning of the training period, however, IGF-I presented higher concentrations in A3 coinciding with higher jump height results. With these results it was possible to infer that the concentration of IGF-I is positively correlated with the physical performance of volleyball athletes and that the reduction or inability to increase IGF-I may be a warning signal for athletes and coaches. Still, further studies are needed to investigate whether training will have similar effects during long periods of training, more intense training periods, different phases during the preparation or competition period will produce similar hormonal responses.
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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-XL protein, 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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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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Clark, Martin. "Interaction of IGF-I & IGFBP-3 with p53 in cell cycle control." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422577.
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McCarthy, K. "The influence and expression of IGFBP-3 in normal and malignant breast tissue." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444892/.
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The mitogenic and anti-apoptotic effects of insulin-like growth factor-1 (IGF-1) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-3. In vitro studies have demonstrated the importance of the IGF-1 axis in regulating the growth of breast cancer cells. Little is known, however, about the IGF-independent role of IGFBP-3 in breast cancer and the mechanisms regulating its production. We investigated the expression of IGFBP-3 in malignant and paired adjacent normal (n=53), and healthy normal (n=17) breast tissue samples using RT-PCR, immunohistochemistry and ELISA. We compared IGFBP-3 expression with other members of the IGF-I axis, other known tumorigenic genes and clinicopathological parameters. We also developed a novel tissue explant system using fresh normal and malignant breast tissue, with which we examined the in vitro effects of IGFBP-3 alone and in combination with known apoptotic agent, doxorubicin (n=6), on tissue viability and apoptosis. Results demonstrated universal high level of expression of IGFBP-3 mRNA in all types of breast tissue. There was no difference in level of expression between any of the three groups of breast tissue (approaching those seen in the liver where it is predominantly produced). 96% of samples also expressed IGFBP-3 protein. High levels of IGFBP-3 mRNA were associated with the presence of high grade ductal carcinoma-in-situ (p<0.0001), the pre-invasive stage in breast cancer. A significant correlation was also found between IGFBP-3 negative/weakly positive tumours and lymph node negativity (p<0.05), thereby supporting an association between IGFBP-3 and the development of invasive disease. There was, however, no significant correlation between IGFBP-3 expression and other clinicopathological parameters. The in vitro tissue explant system demonstrated that IGFBP-3 had little effect by itself on apoptosis. However, when used in combination with doxorubicin, a marked enhancement of apoptosis was seen in breast tumours. In contrast, less apoptosis was seen in normal breast tissue suggesting a protective effect. These divergent effects suggest a potential novel chemotherapeutic approach in the treatment of breast cancer. These findings suggest that IGFBP-3 may play a role in tumorigenesis. It may therefore be possible in future, that IGFBP-3 levels could be used in cancer risk assessment and prevention or infact, as markers of response to cancer treatments.
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Lemos, Nadiane Albuquerque. "Avaliação de IGF-1 (Insulin-like growth factor-1), IGFBP-1 e IGFBP-3 (Insulin-like to growth binding protein-1 e 3) no fluído folicular de pacientes infertéis com endometriose." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2002. http://hdl.handle.net/10183/2958.
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Le, Hang Thi Thu. "Functional characterization of IGF2BP2, a diabetes-susceptibility gene." Thesis, University of Cambridge, 2011. https://www.repository.cam.ac.uk/handle/1810/283871.
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Carr, Jillian M. "Insulin-like growth factor binding proteins (IGFBPs) in growth and development of the ovine fetus." Adelaide Thesis (Ph.D.) -- University of Adelaide, Department of Biochemistry, 1994. http://hdl.handle.net/2440/21607.
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Bartram, Isabelle [Verfasser]. "Charakterisierung der molekularen Marker BCL11b und IGFBP7 in der akuten T-lymphoblastischen Leukämie / Isabelle Bartram." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1070498300/34.
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César, Edna Samara Ribeiro. "Efeito da suplementação de zinco sobre o GH, IGF-1 e IGFBP3 em idosas saudáveis." Universidade Federal da Paraíba, 2013. http://tede.biblioteca.ufpb.br:8080/handle/tede/4289.
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The aging process involves several physiological changes among them the decrease in anabolic hormones. As a result, more and more researches have been developed in order to improve the quality of life in this population. This research aimed to evaluate the effect of zinc supplementation on serum levels of GH, IGF-1 and IGFBP3 in elderly women. The study included 20 apparently healthy elderly and divided into 2 groups (Supplemented and Placebo). After approval by the Ethics Committee in Research of the Center for Health Sciences UFPB the elderly received 25mg/day of zinc or placebo for 90 days. The parameters were analyzed using the paired Student t test and unpaired GraphPad-Prism software v.5.04. We adopted a significance level of 5% for all tests. It was observed that the values of dietary zinc in both groups showed levels below recommended for the elderly, the control group showed a significant reduction in plasma zinc concentration from the beginning to the end of the experiment, while the supplemented group maintained levels plasma without significant changes in the same period. Zinc supplementation caused a significant increase in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in both groups, but levels remained within the reference values. With regard to hormones zinc supplementation was able to increase the levels of GH and IGFBP3 (p = 0.004 and 0.02, respectively) and tended to increase IGF-1 levels (p = 0.06). It was observed that zinc supplementation produced an increase in serum levels of GH and IGFBP3 tendency to increase IGF-1. Therefore Zinc could be an alternative for increasing GH levels in the elderly without the harmful effects that GH replacement entails.
O processo de envelhecimento envolve várias alterações fisiológicas dentre elas a diminuição dos hormônios anabólicos. Em decorrência disso, cada vez mais pesquisas têm sido desenvolvidas com a finalidade de melhorar a qualidade de vida nessa população. Esta pesquisa teve como objetivo avaliar o efeito da suplementação de zinco sobre os níveis séricos de GH, IGF-1 e IGFBP3 em idosas. Foi desenvolvido um estudo clínico, randomizado, duplo cego com placebo controlado. Inicialmente foram selecionadas 56 idosas e após os critérios de exclusão participaram 20 idosas que foram divididas em 2 grupos: Zinco (n=10) e Placebo (n=10). Após a aprovação pelo Comitê de Ética em Pesquisa do Centro de Ciências da Sáude da UFPB as idosas receberam 25mg/dia de zinco ou placebo por 90 dias. Os parâmetros foram analisados por meio do teste t student no software GraphPad-Prism v.5.04. Adotou-se um nível de significância de 5% para todos os testes. Observou-se que os níveis de zinco dietético apresentaram-se abaixo do recomendado para os idosos no grupo zinco (5,7 ± 0,68 mg/dia ) e placebo (6,5 ± 0,66 mg/dia ). O grupo controle sofreu uma redução significativa na concentração de zinco plasmático do inicio até o final do experimento (1,0 ± 0,01 para 0,9 ± 0,02), enquanto que o grupo suplementado manteve os níveis plasmáticos sem alterações significativas neste mesmo período (1,0 ± 0,03 para 1,0 ± 0,04). As idosas de ambos os grupos apresentaram aumento das enzimas aspartato aminotransferase (AST) e alanina aminotransferase(ALT) após a suplementação, no entanto os níveis mantiveram-se dentro dos valores de referência. Com relação aos hormônios a suplementação de zinco foi capaz de aumentar os níveis de GH (p< 0,004) e IGFBP3 (p<0,02), embora o grupo zinco não tenha apresentado níveis hormonais melhores que o grupo placebo. O efeito do zinco foi superior ao do placebo, porém de pequena magnitude. Portanto, não podemos descartar a possibilidade do zinco ser uma alternativa para aumentar os níveis de GH em idosos, necessitando, portanto, a realização de outras pesquisas com um N maior.
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Baude, Anne [Verfasser], Stefan [Gutachter] Hüttelmaier, Elmar Gutachter] Wahle, and Dirk H. [Gutachter] [Ostareck. "Zusammensetzung von IGF2BP1-enthaltenden Ribonukleoproteinkomplexen / Anne Baude ; Gutachter: Stefan Hüttelmaier, Elmar Wahle, Dirk H. Ostareck." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2019. http://d-nb.info/1210732068/34.
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Baude, Anne [Verfasser], Stefan [Gutachter] Hüttelmaier, Elmar [Gutachter] Wahle, and Dirk H. [Gutachter] Ostareck. "Zusammensetzung von IGF2BP1-enthaltenden Ribonukleoproteinkomplexen / Anne Baude ; Gutachter: Stefan Hüttelmaier, Elmar Wahle, Dirk H. Ostareck." Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2019. http://d-nb.info/1210732068/34.
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Kricker, Jennifer Ann. "Structural investigations into the relationships of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) with vitronectin (VN)." Thesis, Queensland University of Technology, 2005. https://eprints.qut.edu.au/16063/1/Jennifer_Kricker_Thesis.pdf.
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Previous studies demonstrated that IGF-II binds directly to vitronectin (VN) while IGF-I binds poorly. However, binding of VN to integrins has been demonstrated to be essential for a range of IGF-I-stimulated biological effects including IGF binding protein-5 (IGFBP-5) production, IGF type-1 receptor autophosphorylation and cell
migration. Thus, this study examined the hypothesis that a link between IGF-I and
VN must occur and may be mediated through IGFBPs. Studies using competitive
binding assays with VN and [125I]-labelled IGFs in the absence and presence of
IGFBPs revealed IGFBP-4, IGFBP-5 and non-glycoyslated IGFBP-3 significantly
enhance binding of IGF-I to VN, while IGFBP-2 and glycosylated IGFBP-3 had a
smaller effect. Furthermore, binding studies with analogues indicate that
glycosylation status of IGFBP-3 and the heparin-binding domains of IGFBP-3 and
IGFBP-5 are important in this interaction. The functional significance of IGFs
binding to VN on cell migration in MCF-7 breast carcinoma cells was examined and
cell migration was found to be enhanced when VN was pre-bound to IGF-I in the
presence of IGFBP-3, -4 and -5. The effect required IGF:IGFBP:VN complex
formation; this was demonstrated by use of a non-IGFBP-binding analogue, des(1-
3)IGF-I. Additionally, higher doses of IGFs in the presence of VN also could
stimulate cell migration. Together, these data indicated the importance of IGFBPs
in modulating IGF-I binding to VN and that this binding has functional
consequences in cells. Future directions for this work include investigations into the
mechanisms underlying formation of the trimeric complex and the associated
signalling pathways involved.
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McDonnell, Lisa. "The effects of growth hormone on primary bovine mammary cell models." DigitalCommons@CalPoly, 2012. https://digitalcommons.calpoly.edu/theses/868.
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The ability of exogenous growth hormone (GH) to increase milk yield through insulin-like growth factor-1 (IGF-I) in dairy cows is well characterized. However, recent studies utilizing mammary epithelial cell lines indicate a direct effect of GH on mammary epithelial cells (MEC). To test if these observations are relevant in vivo and if this response differs between dairy breeds, three mammary models were utilized. Mammary explants from a lactating Jersey cow were cultured in classical lactogenic media (dexamethasone, insulin, and prolactin) with 0 or 10 ng/mL of recombinant bovine GH for 12h. Primary MEC from lactating Holstein and Jersey cows were cultured in classical lactation media with 0 or 10 ng/mL of GH for 2, 4, and 7 days. And lastly, MEC isolated from pooled Holstein or pooled Jersey milk were cultured in the same conditions as primary MEC. The response to GH was quantified by the relative abundance of mRNA for two milk protein genes (α-lactalbumin and αS1-casein), the GH receptor, IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) as determined by quantitative RT-PCR. The abundance of α-lactalbumin mRNA in explants was increased in response to GH. After 2 days, Jersey primary MEC showed an increase in GH receptor mRNA, in addition to a noteworthy trend of increasing abundance of IGFBP-3 regardless of GH treatment. After 4 days, Holstein primary cells cultured with GH had decreased IGFBP-3 mRNA. After 7 days, primary cells isolated from Holstein and Jersey mammary tissue showed a slight response to GH. Mammary cells from milk mirrored the responses to GH observed in primary cells: MEC isolated from Holsteins had decreased IGFBP-3 mRNA after 4 days of treatment with GH and MEC isolated from Jerseys showed the same trend of increasing IGFBP-3 abundance between 2 and 4 days, but with no difference between GH treatments. These results indicate that the effect of GH may differ between breeds and indicate GH has a direct effect on mammary epithelial cells, possibly including effects on the abundance of IGFBP-3 mRNA.
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Muhlbradt, Erin Elizabeth. "IGFBP-3 mediates the effect of tumor suppressor NKX3.1 on prostate cancer cell proliferation." Connect to Electronic Thesis (CONTENTdm) Connect to Electronic Thesis (ProQuest), 2008. http://worldcat.org/oclc/642191611/viewonline.
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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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Fowler, Darren Joseph. "Placental and fetal IGF/IGFBP expression and chorionic villus behaviour in early human pregnancy." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409661.
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Chua, Melissa Wan Ying. "The role of IGFBP-3 in breast cancer cell response to DNA-damaging therapy." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13730.
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Background: Triple-negative breast cancer is an aggressive form of breast cancer, not treatable by current targeted therapies and with a tendency to acquire resistance to conventional therapies. It is therefore crucial to negate the drivers of these malignancies in order to improve therapeutic sensitivity. A major cause of resistance to radiotherapy and some chemotherapy is the ability of breast cancer cells to aberrantly repair DNA double strand breaks (DSBs), fueling tumour progression. Irreparable cancer cells may either die or develop pro-survival pathways. Insulin-like growth factor binding protein-3 (IGFBP-3) was previously shown to translocate into the nucleus following DNA damage, where it forms complexes with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and epidermal growth factor receptor (EGFR). This finding, demonstrated in triple-negative breast cancer cells, was the first connection drawn between IGFBP-3 and DNA repair. Aims: The first aim of this study was to ascertain the point at which IGFBP-3 becomes involved in the DNA damage response. The second aim concerned IGFBP-3 as a determinant of cell fate following the initial DNA repair. Methods: The Hs578T human breast cancer cell line was used in this study as these cells express high endogenous levels of IGFBP-3 and phenotypically represent triple-negative breast cancer. The role of endogenous IGFBP-3 was determined using a stable loss-of-function approach, in which IGFBP-3 expression was silenced using short-hairpin RNA (shRNA). Neocarzinostatin (a radiomimetic agent) and etoposide (a topoisomerase II inhibitor) were used to induce DNA DSBs. Results: Etoposide and neocarzinostatin activated the ATM-p53-H2AX axis early following drug exposure, as measured by immunoblotting. This was followed by the phosphorylation of EGFR at Tyr1068. Autophosphorylation of DNA-PKcs at Ser2056 occurred at a later stage of DNA damage, whereas its phosphorylation at Thr2609 varied depending on the DNA-damaging agent used. Using stable knockdown of IGFBP-3, no evidence was found for the regulation of DNA damage and repair signalling by endogenous IGFBP-3. However, transient IGFBP-3 knockdown significantly inhibited DNA-PKcs phosphorylation four hours after etoposide treatment, consistent with previous findings. IGFBP-3 appeared to have no role in the activation of ATM or its substrates p53 and H2AX, suggesting that its involvement in DNA damage repair does not occur upstream of EGFR-DNA-PK activation. IGFBP-3 stable knockdown potentiated the etoposide- and neocarzinostatin-induced loss of cell viability, measured by the MTS assay. However, cell colony formation did not appear to be regulated by endogenous IGFBP-3. With prolonged exposure to etoposide, IGFBP-3 knockdown potentiated PARP-1 cleavage while, surprisingly, it inhibited caspase-3 cleavage. Autophagic flux, measured as LC3-II, increased with etoposide treatment, the increase being attenuated in IGFBP-3 knockdown cells concomitantly with increased PARP-1 cleavage. Conclusions: The data presented in this thesis suggest that chronic IGFBP-3 downregulation is not inhibitory to DNA damage and repair signalling, implying that a compensatory mechanism occurs to negate the effect seen with short-term IGFBP-3 knockdown. They also indicate that the involvement of IGFBP-3 in DNA damage repair does not occur earlier than DNA-PK activation. It is concluded that under some conditions IGFBP-3 may inhibit the pro-apoptotic effects of chemo- and radiotherapeutic agents, culminating in cell survival, consistent with the poor prognosis of women with ER-negative breast cancers with high IGFBP-3 expression.