Research Area: Role of Inflammation in ageing associated Pathologies
1. Research Background:
Inflammation is a primarily beneficial response to injury or infection that is important for host defense and wound healing. However, excessive and/or prolonged inflammatory responses contribute to the pathogenesis of severe diseases. Moreover, an elevated steady state inflammatory tone during aging, often termed ‘inflammaging’, contributes to aging associated diseases and also regulates organismal life span. Therefore, the maintenance of a healthy tissue homeostasis with well-regulated immune responses is critical for the prevention of inflammatory diseases as well as for healthy aging. Tissue homeostasis depends on the balanced interactions between epithelial, stromal and immune cells with the commensal microbes that colonize many tissues in multicellular organisms. Receptors detecting microbes, such as Toll-like receptors, and cytokines, such as TNF receptors, regulate inflammation by activating NF-κB but also triggering regulated cell death pathways, including 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. Recent work by our group and others identified the interplay between NF-κB and cell death signalling as a key regulator of inflammation. A key challenge remains to understand the molecular and cellular mechanisms regulating chronic inflammation, which will be necessary for the development of new targeted therapies for the treatment of inflammatory diseases. Moreover, the contribution of chronic inflammation in the aging process remains to be experimentally validated in suitable model organisms.
2. Research questions addresses by the group:
Our group studies the mechanisms that control immune responses and regulate inflammation, 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-κB 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-κB 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.
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