The course times are not decided yet. The research project will be carried out in the lab of the Biochemistry group. Please contact Prof. Koch for individual timing .
The course times are not decided yet. Practical part:
During infection, bacteria, such as Yersinia enterocolitica, can actively translocate anti-inflammatory proteins into the host cell cytoplasm to suppress the host immune response. These proteins can be produced recombinantly and are to be formulated as drugs for therapy. For this purpose, the mouse model of imiquimod-induced psoriasis-like skin inflammation was used, and the animals were treated with the bacterial compounds. After the efficacy has been proven based on the reduction in disease severity, the mechanism of action shall be analyzed in detail. For this purpose, the induction of apoptosis, the inflammasome activation, cytokine production and NF-B activation or the effect of the proteins on the integrity of the epithelial barrier will be analyzed within this research module. Methods such as multicolor immunofluorescence, multiplex assays for cytokine quantification and characterization of signaling cascades, RNA sequencing or kinome analysis will be used.
Theoretical part (seminar):
During the research module, the pathomechanisms of chronic inflammatory skin diseases will be discussed, with a specific focus on the involvement of the immune system in the development of psoriasis vulgaris. At the same time, various possibilities how bacterial pathogens evade host immune defenses will be presented. These possibilities include the production of cell-penetrating peptides (CPEs) with anti-inflammatory properties, which can be developed as agents for therapy (drugs-from-bugs concept).
The course times are not decided yet. Objectives
The endogenous opioid system plays an important role in the pathogenesis of inflammatory disorders and opioid receptor agonists, mainly agonists of the kappa-opioid receptor (KOR), are able to regulate cytokine production, immune cell activation and migration. Therefore, activation of KOR could represent a novel promising approach for the treatment of (sterile) inflammation. Therefore, we developed quinoline- and quinoxaline-based KOR agonists with high affinity, selectivity, and full agonistic activity. These KOR agonists reduced the production of pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF, IFN-y) as well as immune cell proliferation upon activation. The observed effects were mediated via KOR signalling, since off-target effects were excluded by using KOR deficient mouse mutants.
Now we intend to develop new KOR agonists based on novel scaffolds. In particular, diverse substituents in 4- or 5-position of the perhydroquinoline system allow versatile modifications allowing fine-tuning of pharmacodynamic and pharmacokinetic properties. These novel KOR agonists will be used to better understand the relevance of KOR signalling in inflammatory diseases. Hence, the effect of KOR agonists on phenotype, function and migratory activity will be analyzed in primary mouse and human immune cells by multicolor flow cytometry, multiplex bead assays or impedance-based measurements using the xCELLigence®-system). Moreover, the metabolic activity and transcription profile of immune cells treated with KOR agonists shall be assessed using the Seahorse® technology and (single cell) RNA sequencing.
The course times are not decided yet. The research project will be carried out in the lab of the Biochemistry group. Please contact Prof. Koch for individual timing .
The course times are not decided yet. Practical part:
During infection, bacteria, such as Yersinia enterocolitica, can actively translocate anti-inflammatory proteins into the host cell cytoplasm to suppress the host immune response. These proteins can be produced recombinantly and are to be formulated as drugs for therapy. For this purpose, the mouse model of imiquimod-induced psoriasis-like skin inflammation was used, and the animals were treated with the bacterial compounds. After the efficacy has been proven based on the reduction in disease severity, the mechanism of action shall be analyzed in detail. For this purpose, the induction of apoptosis, the inflammasome activation, cytokine production and NF-B activation or the effect of the proteins on the integrity of the epithelial barrier will be analyzed within this research module. Methods such as multicolor immunofluorescence, multiplex assays for cytokine quantification and characterization of signaling cascades, RNA sequencing or kinome analysis will be used.
Theoretical part (seminar):
During the research module, the pathomechanisms of chronic inflammatory skin diseases will be discussed, with a specific focus on the involvement of the immune system in the development of psoriasis vulgaris. At the same time, various possibilities how bacterial pathogens evade host immune defenses will be presented. These possibilities include the production of cell-penetrating peptides (CPEs) with anti-inflammatory properties, which can be developed as agents for therapy (drugs-from-bugs concept).
The course times are not decided yet. Objectives
The endogenous opioid system plays an important role in the pathogenesis of inflammatory disorders and opioid receptor agonists, mainly agonists of the kappa-opioid receptor (KOR), are able to regulate cytokine production, immune cell activation and migration. Therefore, activation of KOR could represent a novel promising approach for the treatment of (sterile) inflammation. Therefore, we developed quinoline- and quinoxaline-based KOR agonists with high affinity, selectivity, and full agonistic activity. These KOR agonists reduced the production of pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF, IFN-y) as well as immune cell proliferation upon activation. The observed effects were mediated via KOR signalling, since off-target effects were excluded by using KOR deficient mouse mutants.
Now we intend to develop new KOR agonists based on novel scaffolds. In particular, diverse substituents in 4- or 5-position of the perhydroquinoline system allow versatile modifications allowing fine-tuning of pharmacodynamic and pharmacokinetic properties. These novel KOR agonists will be used to better understand the relevance of KOR signalling in inflammatory diseases. Hence, the effect of KOR agonists on phenotype, function and migratory activity will be analyzed in primary mouse and human immune cells by multicolor flow cytometry, multiplex bead assays or impedance-based measurements using the xCELLigence®-system). Moreover, the metabolic activity and transcription profile of immune cells treated with KOR agonists shall be assessed using the Seahorse® technology and (single cell) RNA sequencing.
The course times are not decided yet. Please contact Dr. Ulrike Meyer for individual timing and further information
Hinweise zum Modul
Prerequisites
as defined in the admission and examination regulations
Module examination
graded: project report
ungraded: participation in seminar and 30 min. presentation
Skills to be acquired in this module
Competencies:
++ deepened biological and / or clinical expertise
++ deepened knowledge of biological working methods and / or clinical diagnostics
++ data analysis skills
+ interdisciplinary thinking
++ critical and analytical thinking
++ independent searching and knowledge of scientific literature
++ ability to perform independent biological research
++ data presentation and discussion (written and spoken)
+ team work
+ ethics and professional behaviour
+ project and time management
