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Functional in vivo characterization of Neprilysin as a central regulator of insulin signaling and muscle contraction in Drosophila melanogasterSchiemann, Ronja Thea 14 October 2022 (has links)
Peptides play pivotal roles in the regulation of various physiological processes. As neuropeptides or peptide hormones, they can bind to a range of receptors and thereby trigger the activation of different pathways, including insulin signaling. Another central functionality is facilitated by the action of the as regulins summarized transmembrane micropeptides. By binding to the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), the regulins control Ca2+ homeostasis and muscle contraction. With the ongoing identification of novel modulatory micropeptides encoded by small open reading frames, the urgency to understand peptide-dependent regulatory networks rises. In this regard, especially impact and physiological relevance exerted by the enzymatic inactivation of the mature, biologically active peptides are far from completely understood.
Neprilysins are metalloendopeptidases expressed throughout the animal kingdom. Based on their broad substrate specificity, the activity of neprilysins is crucial for the modulation of multiple peptide-dependent processes. This work aimed to identify new peptide substrates of the Drosophila melanogaster Neprilysin 4 (Nep4) and investigate the enzyme's physiological impact on the affected regulatory mechanisms.
The first part of the work could identify 16 novel Nep4 peptide substrates that play essential roles in insulin signaling and the regulation of food intake: allatostatin A1-A4, adipokinetic hormone, corazonin, diuretic hormone 31, drosulfakinin 1 and 2, leucokinin, two short neuropeptide F peptides, and tachykinin 1-4. Thereby, aberrant expression of Nep4 leads to severe phenotypes linked to misregulation of insulin signaling, including reduced body size and weight, compromised food intake, and a characteristic shift in metabolomic composition.
To further investigate and understand the complex functionality of the newly discovered Nep4 substrates, these peptides were tested for their ability to modulate the Drosophila heartbeat. A combined in vitro/in vivo screen revealed that the tested substrates exert chronotropic as well as inotropic effects, rendering the peptides as essential novel modulators of the heartbeat in Drosophila.
The main project of this thesis was based on the initial finding that animals with Nep4 overexpression exhibit severe impairments of body wall muscle and heart functionality. By applying various experiments, including analyses of muscle and heart contraction, measurement of Ca2+ transients, pull-down studies, STED super-resolution microscopy, and mass spectrometry, Neprilysin 4 was identified as a novel modulator of SERCA activity. The molecular underpinning of this regulatory mechanism is the Nep4 mediated cleavage and inactivation of Drosophila SERCA-inhibitory Sarcolamban micropeptides SCLA and SCLB. Strikingly, cleavage experiments using the mammalian neprilysin and apparent colocalization of Neprilysin and SERCA in human heart tissue indicate evolutionary conservation of this mechanism.
In summary, this work could identify a range of so far unknown Nep4 substrates and thereby point out the critical roles these class of enzymes plays in insulin signaling as well as the physiology of muscle and heart contraction.
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Differentielle Genexpressionsanalyse aktivierter Endothelzellen / Differential genexpression-analysis of activated endothelial cellsSchmidt, Tobias 30 April 2001 (has links)
No description available.
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Untersuchungen zu Nitrat-induzierbaren Proteinen der Plasmamembran von Chlorella saccharophila (Krüger) Nadson / Investigations on nitrate-inducible proteins in the plasma membrane of Chlorella saccharophila (Krueger) NadsonBrechlin, Peter 30 October 2002 (has links)
No description available.
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Zellbiologie der Knochenresorption / Osteoklasten und aktivierte Fibroblasten im Resorptionsassay / Cellbiology of Bone Resorption / Osteoclasts and activated fibroblasts in a resorptionsassayClaus, Anja Ilse 29 October 2002 (has links)
No description available.
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Einschränkung hepatischer Abwehrreaktionen während einer Entzündung durch Prostaglandin E2 über Gs-Protein-gekoppelte Prostaglandin E2-Rezeptoren / Restriction of hepatic defence reactions during an inflammation by prostaglandin E2 via Gs-protein-coupled prostaglandin E2 receptorsFennekohl, Alexandra 30 October 2001 (has links)
No description available.
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Interaktion von Leukozyten mit endothelialen Adhäsionsmolekülen und ihre Inhibition durch Expression von konkurrierenden Fusionsproteinen / Interactions of leukocytes with endothelial adhesion molecules and the inhibition by expression of competing fusion proeinsMarheineke, Sabine 25 April 2002 (has links)
No description available.
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Insulin-Like Growth Factor Binding Protein-6: Posttranslational modifications and sorting in polarized MDCK cells / Insulin-ähnlicher Wachstumsfaktor Bindungsprotein 6: Posttranslationale Modifikationen und Sortierung in polarisierten MDCK ZellenShalamanova-Malinowski, Liliana Dimitrova 30 October 2001 (has links)
No description available.
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Role of the mGRIP1 homologue DGrip in the Drosophila neuromuscular system / Rolle des mGRIP1-homologs, DGrip, in dem Neuromuskulaeren System der Fruchtfliege Drosophila melanogasterSwan, Laura 21 April 2005 (has links)
No description available.
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Kompartementalisierung des Kohlenhydrat-Stoffwechsels in Toxoplasma gondii / Compartementation of the C-Metabolism in Toxoplasma gondiiFleige, Tobias 01 November 2006 (has links)
No description available.
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Regulation des mitochondrialen Zerfalls innerhalb der neuronalen Apoptose / Regulation of mitochondrial fission during neuronal apoptosisMeuer, Katrin 02 May 2007 (has links)
No description available.
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