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Effects of ghrelin and its novel endogenous antagonist LEAP2 and their role in obesity
Tureckiová, Theodora ; Maletínská, Lenka (advisor) ; Selicharová, Irena (referee)
Obesity is a very dangerous metabolic disease, caused by the development of resistance to the anorexigenic (food intake reducing) hormone leptin, with an ever-increasing prevalence. Recently, both anorexigenic peptides and orexigenic (food intake increasing) peptide antagonists have emerged as candidates for the development of anti-obesity treatment. An example of such a peptide is the newly discovered endogenous ghrelin antagonist known as liver enriched antimicrobial peptide 2 (LEAP2). The uniqueness of the relationship between ghrelin and LEAP2 lies in the unusual occurrence of agonists and antagonists of the same receptor within the same organism. This receptor, known as growth hormone secretagogue receptor 1a (GHSR1a), is, among other roles, responsible for increased food intake and weight gain. Natural ghrelin and LEAP2 analogues, specifically non-lipidized LEAP2(1-14) fragment and lipidized (palmitoylated) palm-LEAP2(1-14) were used for studying their properties. The aim of this study was to demonstrate binding properties of LEAP2 analogues to the GHSR1a and to compare the effect of the lipidized analogue versus the non- lipidized one in vitro. Effects of the lipidated analogue were further investigated in vivo. Results of in vitro experiments demonstrated the binding of both LEAP2 analogues...
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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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Study of activation properties of insulin, IGF-1 and IGF-2 analogs towards the receptors for insulin and IGF-1
Chrudinová, Martina ; Selicharová, Irena (advisor) ; Šulc, Miroslav (referee) ; Skálová, Lenka (referee)
The insulin/insulin-like growth factor signaling axis is a complex system that is involved in the regulation of metabolism and body growth. It includes three related peptide hormones: insulin and two insulin-like growth factors (IGF-1 and IGF-2), and their receptors: two isoforms of insulin receptor (IR-A and IR-B), and IGF-1 receptor (IGF-1R). Whereas insulin is involved predominantly in regulation of the metabolism, IGFs participate mainly in the regulation of cell growth, proliferation and differentiation. Due to the similarities in the structures of both the hormones and the receptors, all the hormones can bind and activate all the receptors, although with different potencies. At which point and how are the "metabolic" and "mitogenic" functional outcomes of the system diversified, as well as the structural determinants responsible for the different affinities of the hormones to the individual receptors, is still not completely understood. Deregulation of the insulin/IGF system can result in many types of pathological states, mainly diabetes mellitus and cancer. Therefore, to deeply understand the functioning of the insulin/IGF system to the structural details is crucial for development of analogs with desirable properties, that are of great clinical interest. First of all, we developed a...
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