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New insulin-like growth factor 1 (IGF-1) analogs for receptor studies and therapeutic applications
Lin, Jingjing ; Jiráček, Jiří (advisor) ; Hodek, Petr (referee) ; Lapčík, Oldřich (referee)
The insulin/IGF system is an evolutionary conserved network that includes three closely related peptide hormones (insulin, IGF-1 and IGF-2), three homologous tyrosine kinase receptors (IR-A, IR-B and IGF-1R), a distinct IGF-2 receptor (IGF-2R), and six IGF-binding proteins. While insulin signals mainly via IR, playing a key role in glucose homeostasis, IGFs mainly signal via IGF-1R to mediate normal human growth. A tight control of ligands and receptors expression is crucial for the proper functioning of the organism. Aberrant signaling by these receptors is manifested in many pathological conditions, including cancer, growth disorders, neurodegenerative diseases and diabetes. Hence, the insulin/IGF axis represents a promising therapeutic target. In view of the multiple unsuccessful clinical anticancer trials performed either with tyrosine kinase inhibitors or antibodies targeted against IGF-1R, the development of novel selective and receptor-specific insulin and IGF analogs with minimized side effects would be of interest. Our study began with the recombinant preparation of IGF-1 dimers in which IGF-1 monomers are interlinked between their C- and N-termini with Ser-Gly linkers (length of 8, 15 or 25 residues). The goal was to investigate whether the binding of two covalently linked IGF-1 molecules...
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Role of Arginine 717 in insulin receptor respective Arginine 704 in IGF-1 receptor for the interaction with ligands
Kertisová, Anna ; Selicharová, Irena (advisor) ; Ryšlavá, Helena (referee)
Insulin and insulin-like growth factor 1 (IGF-1) are peptide hormones that are important regulators of cellular metabolism, proliferation and apoptosis. Disruptions in signalling pathways may cause a whole range of diseases from diabetes mellitus type 1 and type 2 to cancer or neurodegenerative diseases. The cellular response to these hormones is mediated by insulin (IR) and IGF-1 receptors (IGF-1R) with a tyrosin-kinase activity. Receptors are created as hetero-tetramers of two extracellular α-subunits and two intracellular β-subunits. Studies of receptor structures try to elucidate the basic principles of the interaction of receptors with their ligands. However, the role of some amino-acid residues in binding remains unclear. It was suggested that the arginine 704 of IGF-1R may interact with Glu58 IGF-1. In comparison with IGF-1R, the equivalent arginine 717 IR was not associated with an important role in insulin binding in previous studies. This thesis is focused on clarifying the role of Arg704 IGF-1R and for comparison analogically on Arg717 IR isoform A (IR-A) in ligand binding to the receptors. Therefore, mutant variants of IGF-1R in positions His697 and Arg704 and variants IR-A in positions His710 and Arg717 were created. The role of histidines 697 IGF-1R and 710 IR was already elucidated...
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Analogues of IGF-1 for the study of interactions of the hormone with the receptors for IGF-1 and insulin
Macháčková, Kateřina ; Jiráček, Jiří (advisor) ; Obšilová, Veronika (referee) ; Šulc, Miroslav (referee)
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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Analogues of IGF-1 for the study of interactions of the hormone with the receptors for IGF-1 and insulin
Macháčková, Kateřina
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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Analogues of IGF-1 for the study of interactions of the hormone with the receptors for IGF-1 and insulin
Macháčková, Kateřina
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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Analogues of IGF-1 for the study of interactions of the hormone with the receptors for IGF-1 and insulin
Macháčková, Kateřina ; Jiráček, Jiří (advisor) ; Obšilová, Veronika (referee) ; Šulc, Miroslav (referee)
Insulin/IGF system is a complex network of three similar hormones (insulin, IGF-1 and IGF-2) and their three similar receptors (IR-A, IR-B and IGF-1R,), which play important roles in maintaining basal energy homeostasis of the organism, in growth, development, life-span but also in development of diseases such as diabetes mellitus, cancer, acromegaly or Laron dwarfism. Despite structural similarities between family members, each member have its unique role in the system. Identification of structural determinants in insulin and IGFs that trigger their specific signalling pathways is important for rational drug design for safer treatment of diabetes or for more efficient combating of cancer or growth-related disorders. In this thesis, we focused on identification of such structural determinants in IGF-1. Comparison of our data with parallel studies with IGF-2 and insulin could give a more complex picture of the problem. First of all, we developed necessary methodologies for the preparation of IGF-1 analogues. We developed a new methodology for the total chemical synthesis of IGF-1 analogues based on the solid-phase synthesis of fragments and their ligation by a CuI -catalyzed cycloaddition of azides and alkynes. In parallel, we developed a procedure for a recombinant production of IGF- 1 and its...
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Intrauterine growth retardation (IUGR / SGA) - causes, clinical view, consequences
Kročilová, Kateřina ; Sedlak, Petr (advisor) ; Čermáková, Ivana (referee)
Deficient intrauterine growth may point to a serious health problem of fetus. It is associated with increased perinatal and neonatal mortality and morbidity. Long-term health consequences have been reported in IUGR / SGA children. There are many factors leading to intrauterine growth retardation. What is important is early diagnosis and distinction of children with prenatal growth deficiency (IUGR) and children constitutionally small for gestational age (SGA). This bachelor thesis summarizes basic knowledge of this disease and describes the various practices for the treatment of growth hormone.
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Hormonal Aspects of Antler Growth Regulation
Kužmová, Erika ; Bartoš, Luděk (advisor) ; Petr, Jaroslav (referee) ; Kierdorf, Uwe (referee)
Hormonal aspects of antler growth regulation Erika Kužmová Abstract Deer antlers are the only mammalian organ that completely regenerates and therefore they became an object of rising interest as a potential model for bone growth and development. In recent years, it has been confirmed that annual regeneration of the antler is initiated from the stem cell niche localised in the pedicle periosteum. Antlers grow to the length at the tip. Only a little is known about endocrine stimulation of antler growth and some discrepancy has arisen between in vivo and in vitro studies over the decades. As the secondary sexual character, the antler cycle timing and growth are linked to seasonal levels of testosterone. Since the levels are at their minimum during the antler growth phase, according to many mainly in vitro studies, insulin-like growth factor-1 (IGF-1) tends to be accepted as the "antler stimulating hormone". Since the conclusion about the role of IGF-1 was contradictory to previous opinions and also in contrast with our own experience, we aimed to verify the role of IGF-1 in vitro. Our ex- periments were based on existing in vivo studies demonstrating the importance of testosterone, even in its low levels, and on the hypothesis that testosterone should be the "antler stimulating hormone". We performed in vitro...
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