Prof. Dr. Manolis Pasparakis

Research Area: Inflammation in Aging-Associated Diseases


1. Research Background:

Healthy tissue homeostasis is maintained by balanced interactions between epithelial, stromal and immune cells with the commensal microbes that normally reside on the surface of our barrier tissues such as the gut and the skin. Disruption of tissue homeostasis can cause inflammation and result in disease. Inflammation is a primarily beneficial reaction that is important for host defense and wound healing. However, excessive and/or prolonged inflammatory responses contribute to the pathogenesis of severe diseases, therefore immune responses need to be stringently regulated to ensure efficient host defense and prevent tissue damage and disease. Receptors detecting microbes, such as Toll-like receptors, or cytokines, such as TNF receptors, regulate inflammation by activating NF-kB but also triggering regulated cell death pathways, namely apoptosis and necroptosis. TNF is a potent immunoregulatory cytokine with an important role in host defense but also in the pathogenesis of chronic inflammatory diseases including Inflammatory bowel disease, psoriasis and arthritis. However, the mechanisms by which TNF causes inflammatory diseases remain poorly understood.

2. Research questions addresses by the group:

Our group studies the mechanisms that regulate immune responses, with particular interest on identifying molecules and pathways that contribute to the pathogenesis of chronic inflammatory diseases. We have a long-standing interest on understanding how TNF and NF-κB signalling contributes to tissue homeostasis and disease pathogenesis. We focus particularly on barrier tissues such as the intestine, the skin and the lung, which constitute interfaces between the body and the environment where the cross-talk between microbes and host immune cells needs to be tightly controlled. We are interested to understand the mechanisms regulating TNF-induced NF-kB signalling and its role in inflammation and cell death. A key research interest is also to dissect the mechanisms controlling apoptosis and necroptosis and how these pathways of regulated cell death contribute to host defense, inflammation and disease. On the molecular level, we study the role of key regulators of inflammatory and cell death signalling, including IKK subunits and NF-kB proteins, RIP kinases, E3 ubiquitin ligases and DUBs as well as adapter proteins important for the formation and regulation of the different signalling hubs that control inflammatory gene expression, apoptosis and necroptosis. Our long-term goal is to understand at the molecular level the mechanisms that regulate immune homeostasis and control inflammation and use this knowledge to identify new therapeutic targets for the treatment of chronic inflammatory diseases.

3. Possible projects:

Multiple projects are available to study questions relevant to the molecular and cellular mechanisms regulating cell death and inflammation.

4. Applied Methods and model organisms:

We use 'state of the art' genetic mouse models to study the mechanisms regulating tissue homeostasis and inflammation in vivo. We apply CrispR/Cas9 gene targeting methodologies to genetically dissect the role of key regulators of inflammation and cell death. We use primary cells from genetic mouse models but also genetically engineered cell lines for molecular and biochemical mechanistic studies. All modern methodologies for the molecular, biochemical and genetic study of molecules and pathways are applied in our lab.

5. Desirable skills and qualifications:

Excellent basic background knowledge in molecular & cellular biology, genetics and biochemistry.

6. References:

  • Lin J, Kumari S, Kim C, Van TM, Wachsmuth L, Polykratis A, Pasparakis M (2016) RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540: 124-128
  • Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517: 311-20
  • Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, Eftychi C, Lin J, Corona T, Hermance N, Zelic M, Kirsch P, Basic M, Bleich A, Kelliher M, Pasparakis M (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513: 90-4
  • Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G, Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477: 330-4
  • Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B, Gumucio D, Neurath MF, Pasparakis M (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446: 557-61