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Forschungsprojekt aus §26 oder §27 Mitteln
Laufzeit : 2021-06-01 - 2022-05-31

Strain and process improvement is one of the most labor-intensive and time-consuming phases of biotechnology process development. High-throughput screening is usually in miniaturized static cultures which compromises scalability, so that further intermediate screening steps are needed. Maturing of existing technology to deal with additional cell culture types (i.e. mammalian cells) and incorporate further analytical developments to support metabolite and product screening requirements are identified as the key steps to creating a technology of commercial value. In this project, we propose to mature an existing µ-screening platform with two major pillars addressing these steps. Firstly, extending the applicability of the module to fermentation technology based on Chinese Hamster Ovary (CHO) cultures. Secondly, to expand the analytical value of the platform using a combination of valve technology and mass spectrometry to develop a fully integrated platform suitable for application in biotechnology facilities.
Forschungsprojekt aus §26 oder §27 Mitteln
Laufzeit : 2020-03-01 - 2022-11-30

Pflanzliche Zellwände bestehen aus einem komplizierten Verbund verschiedener Polysaccharid-Netzwerke, die essentielle Funktionen im Lebenszyklus der Pflanze übernehmen. Diese Zellwandpolysaccharide stellen interessante Ausgangsstoffe für erneuerbare Materialien und für die Produktion von Biokraftstoffen dar. Um die Wirtschaftlichkeit der Nutzung von Biomasse als erneuerbare Ressource zu verbessern, produzieren Forscher auf der ganzen Welt eine wachsende Anzahl von Pflanzen mit modifizierten Polysaccharid-Zusammensetzungen. Voraussetzung dafür ist jedoch eine genaue Kenntnis der Biosynthese dieser Polysaccharide. Ein von uns kürzlich hergestellter Glycan-Microarray, der mit synthetischen Zellwandoligosacchariden ausgestattet ist, bietet nun zum ersten Mal die Möglichkeit, einen Assay zum simultanen Screening verschiedener pflanzlicher Glycosyltransferasen zu entwickeln. Dazu soll der Microarray mit azido-funktionalisierten Zuckernukleotid-Donoren sowie potentiellen Glycosyltransferasen inkubiert und eingebaute azido-funktionalisierte Monosaccharide anschließend durch Click-Reaktion mit einem Fluoreszenzfarbstoff visualisiert werden. Im Rahmen dieses Projekts sollen die benötigten azido-funktionalisierten Zuckernukleotid-Donoren durch chemische Synthese auf effiziente Weise hergestellt werden.
Forschungsprojekt aus §26 oder §27 Mitteln
Laufzeit : 2020-11-02 - 2023-11-01

Human heme peroxidases figure prominently in human biology by contributing to tissue development and architecture, thyroid hormone biosynthesis and innate immunity. Myeloperoxidase (MPO), eosinophil peroxidase (EPO) and lactoperoxidase (LPO) exhibit an indispensable role in microbial killing by releasing potent antimicrobial oxidants. However, these reaction products may also adversely affect tissues and cause acute and chronic inflammatory diseases. Consequently, there is a need for highly selective inhibitors for MPO, EPO and LPO with no risk of off-target effects, i.e. interference with thyroid peroxidase and peroxidasin 1, which share a similar heme cavity architecture. It has been found that pathogenic bacteria like Staphylococcus aureus have evolved a broad repertoire of strategies to resist microbial killing including SPIN (Staphylococcal Peroxidase INhibitor) that binds tightly to MPO and inhibits its enzymatic activity. SPIN shares no sequence homology to other known proteins and consists of two functionally distinct domains, i.e. a small N-terminal domain which acts as a molecular plug of the access channel and a C-terminal domain which mediates the specific binding to human MPO. This project will characterize the structural basis as well as the thermodynamics and kinetics of binding of SPIN-aureus to and inhibition of MPO including its interference with the individual reaction steps in the halogenation and peroxidase cycle of MPO. We further aim to understand the structure and function of recently identified SPIN-aureus homologs from other staphylococcal species and of an artificially designed SPIN-consensus protein that binds to both MPO and EPO. These investigations will include both comprehensive biochemical and biophysical investigations as well as molecular dynamics simulations. These studies will provide the basis for the design of specific binders and inhibitors for human peroxidases. In detail, we aim to design specific inhibitors for MPO, EPO and LPO employing (i) a rational design including saturation mutagenesis and chemical engineering of the N-terminal plug and (ii) directed evolution of the binding domain for specific interaction with MPO, EPO and LPO using yeast surface display combined with fluorescence activated cell sorting of newly generated SPIN libraries. Summing up, this project will provide (i) the fundamental biochemical understanding of the interaction of SPIN proteins with the human heme peroxidases as well as (ii) will design and select SPIN-based inhibitors of MPO, EPO and LPO. Future studies will focus on the application and further development of these lead candidates as potential drugs in in vitro and in vivo studies.

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