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Archiv-Übersicht     Angebot Nr. 14049

Angebotsdatum: 21. Oktober 2020
Art der Stelle: Doktorarbeit / Diplomarbeit
Fachgebiet: Humanmedizin > Immunologie
Titel des Themas: SASP-tuning via innate immunitypathways

Institut: Interfakultäres Institut für Zellbiologie, Abteilung Immunologie
Adresse:
Prof. Alexander Weber
Auf der Morgenstelle 15
72070 Tübingen
Tel.:    Fax.:
Bundesland: Baden-Württemberg
Homepage: http://https://www.immunology-tuebingen.de/groups/alexander-nr-weber.html?Fsize=%2Fproc%2Fself%2Fgroups%2Fo%27A%3D0%27
E-Mail Kontakt: mail

Beschreibung: The senescence-associated phenotype (SASP) is a key mechanism by which senescent and potentially tumorigenic cells alert the immune system for immune-mediated clearance; however it can also promote cancer progression. Exploitation of the ability of SASP to enlist immune-mediated clearance are highly relevant in cancer therapy, provided ‘bad’ (i.e. tumor-promoting effects ) can be uncoupled from ‘good’ (clearance-promoting) SASP components or effects. Innate immune pathways are essential for triggering and controlling SASP-mediated immune clearance: (1) cGAS-STING induces SASP triggered by cytosolic chromatin (CC) in senescent cells, (2) the NLRP3-caspase axis is a key mediator of inflammation (processing of IL-1 cytokines) promoting SASP cytokines and (3) SASP-triggered surface ligands regulate NK cell clearance. The signaling steps and contribution of senescent vs infiltrating cells in this context of cancer have not been sufficiently elucidated together, neither has the potential for combined cGAS/STING + NLRP3/caspase + NK cell modulation with regard to SASP and immune clearance been studied. Using different senescence models (e.g. oncogene-induced, therapy-induced) we will test the combined effects of cGAS/STING activation and inhibition, NLRP3/Caspase activation and inhibition and MIC-A/B-HLA-E-HLA-C – NGK2A/D/C or KIR ligation or blocking on senescence status, SASP and immune control/clearance in vitro and in vivo. We hypothesize that the three axes are intimately connected in SASP and can be synergistically modulated for decoupling ‘good’ effects from ‘bad’ effects on therapy using small molecular agonists, blocking antibodies or HLA-E peptide ligands. Furthermore, we suggest that specific SASP secretome components or surface molecules may skew ‘good’ vs ‘bad’ SASP effects. Our goal is to identify pathway contributions and ‘skewing’ factors, and convert these insights into new tumor therapies with existing and/or newly developed activators or inhibitors of innate pathways for optimal SASP-mediated immune clearance in the clinic.
Methoden: Immunology (PBMC preparation, cell culture assays of cell lines and primary human and mouse immune cells, ELISA, flow cytometry), molecular biology (mutagenesis, PCR, restriction digests, sub-cloning), protein biochemistry (SDS-PAGE, immunoblot, immunoprecipitation, chromatography), reporter signaling assays, tissue analysis (immunofluorescence), data analysis, scientific writing and presentation.
Anfangsdatum: 11. Januar 2020
Geschätzte Dauer: 3 Jahre
Bezahlung: TV-L E13 65%
Papers: Suggested reading | Glück Nature Cell Biology 2017: Innate Immune sensing of cytosolic chromatin fragments through cGAS promotes senescence | Wiggins Aging 2019: Senescence utilizes inflammatory caspases to drive the SASP | Dou Nature 2018: Cytoplasmic chromatin triggers inflammation in senescence and cancer | Pereira Nature Communications 2019: Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition.
Sonstiges: Please apply electronically to alexander.weber@uni-tuebingen.de with all of the following: Cover/motivation letter (max 1 A4), CV, transcripts and certificate of MSc and BSc degree, support letter from at least 1 previous supervisor. Applications will be reviewed on an ongoing basis and interviews scheduled accordingly.

Team and location | In order to execute this project and complement our laboratory team we hope to recruit additional excellent and enthusiastic researchers, including one PhD student. You would be part of a dynamic research group with a solid track record, and located in an excellent scientific environment, the Department of Immunology at the University of Tübingen, one of Germany’s Excellence Universities. The project represents a collaboration with the labs of Daniel Dauch and Lars Zender (University Hospital) and is embedded in and supported by the local iFIT – Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies". In our well-funded laboratory you would find a friendly, well-connected and international environment, and a firm commitment to good supervision and professional development.

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