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Molecular Signaling in Cell Death and Inflammation: an integrative approach from basic mechanisms to disease models (DISCOBEL)

Research project P7/32 (Research action P7)

Persons :

  • Prof. dr.  VANDENABEELE Peter - Universiteit Gent (RUG)
    Coordinator of the project
    Financed belgian partner
    Duration: 1/4/2017-30/9/2017
  • Dr.  KALAI Michaël - Scientific Institute of Public Health (IPH)
    Financed belgian partner
    Duration: 1/4/2017-30/9/2017
  • Dr.  AGOSTINIS Patrizia - Katholieke Universiteit Leuven (K.U.Leuven)
    Financed belgian partner
    Duration: 1/4/2017-30/9/2017
  • Prof. dr.  PIETTE Jacques - Université de Liège (ULG)
    Financed belgian partner
    Duration: 1/4/2017-30/9/2017
  • Dr.  SAMALI Afshin - National University of Ireland, Galway (UNI-IG)
    Financed foreign partner
    Duration: 1/4/2017-30/9/2017
  • Prof. dr.  FULDA Simone - Universität Ulm (UNI-ULM)
    Financed foreign partner
    Duration: 1/4/2017-30/9/2017

Description :

The inflammatory response is crucial in host defense and recovery from injury. Although it has primarily a
beneficial effect, inflammation can also act as a double-edged sword when not properly controlled.
Consequently, a large number of inflammatory diseases, either acute or chronic, result from deregulation of
important inflammatory checkpoints. These patients suffer from persistent tissue damage caused by
phenomena such as cell death, extracellular matrix reorganization and/or excessive production of
inflammatory cytokines. Many inflammatory stimuli converge on the activation of the transcription
factor NF-B, which drives pro-inflammatory gene expression and survival. Therefore it is of major
importance to understand the different pathways that control NF-B activity. Cell death and inflammation
are intricately inter-related. Excessive cell death, apoptosis or necrosis, can lead to tissue destruction
causing inflammation and/or degeneration, while inflammation modulates cell death responses. Recently,
IAP6/18 network members found that necroptotic cell death (a regulated form of necrotic cell death) can be
at the basis of a number of inflammatory reactions. In addition, many types of stress converge on the
activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER stress) and
autophagy, a tightly-regulated catabolic process involving the degradation of a cell's own components
through the lysosomal machinery. Autophagy has been identified as an important cell death and
inflammation modulating process. NF-B also controls autophagy, which then plays an important role in the
survival of stressed cells. The interaction between inflammation and cell death can also significantly
contribute to carcinogenesis by allowing cell survival and anti-apoptotic mechanisms to become activated.

The modulating role of cell death in inflammation is further witnessed by the fact that dying cells generate
and release danger/damage associated molecular patterns (DAMPs) that trigger or dampen the immune
response and can help in building anti-tumor responses during chemotherapy treatment (e.g. immunogenic
cell death). In addition, changes in the cellular homeostasis of fatty acids production are often required for
cell death resistance. Finally, modulation of cell death and inflammation is crucial in the body’s response to
infectious micro-organisms. However, the precise molecular mechanisms controlling the interplay of
these cellular processes are not yet well understood. Moreover, identifying how these mechanisms
operate at the organism level during inflammatory and infectious diseases, and in cancer is still a major
challenge. We also want to bring fundamental molecular mechanistic insights in the inflammation and cell
death interplay to therapeutic applications.

To this end our network aims (1) to identify molecular mechanisms and signal transduction pathways
that control and regulate cell death and inflammation, (2) to establish their relevance in mouse models of
infectious or sterile inflammatory diseases, and in cancer models available in our network, and (3) to
translate this basic knowledge into potential therapeutic applications. Our network brings together 4
national and 2 international partners with a total of 16 research groups (7 Ugent, 2 KULeuven, 3 Ulg, 2
WIV-ISP, S. Fulda, A. Samali) well recognized within their field, spread over 3 universities (Ugent,
KULeuven and Ulg), one federal institute (WIV-ISP, Brussels) and two international partners (Frankfurt
University, Galway University). This well-balanced network composition and the link with other research
networks (MRP, European projects, Methusalem, Hercules, FWO, IWT-SBO, WelBio) and the existing links
with foreign experts in the specific research areas of this proposal create the required critical mass and
added value that is well above what can be achieved by a single team in a national context. Therefore,
the consortium meetings will really function as small conferences in which multi-faceted research results on
cell death and inflammation are presented, shared and discussed at an early stage.

Objective 1: Identification of molecular mechanisms and signaling pathways in controling cell death
and inflammation.
NF-B signaling controls the expression of multiple pro-inflammatory genes and modulates cell death responses. Deregulated NF-B activation contributes to inflammatory diseases and cancer. NF-B signaling pathways (e.g. so-called classical and alternative NF-B signaling pathways) triggered by inflammatory cytokines (TNF, IL1, IL-33), microbial and endogenous ligands sensed by pattern recognition receptors (TLRs, RIG-I, Nod2), antigen receptors (TcR, BcR), ATP receptors, oncogenic translocations (API2/MALT1), and cellular stress conditions (e.g ER-stress, photo-oxidative stress) will be studied. Several partners within the consortium will study ER-stress induced signal transduction, its crosstalk with NF-B signaling, its regulation and its cell fate outcome (e.g. immunogenic tumor cell death). The research approach is mostly molecule-driven, focusing on key molecules such as ubiquitylation-modulating enzymes (A20, IAPs, CYLD), proteases (MALT1, caspases), lipid-modifying enzymes, and kinases (NIK,
TBK1, IKK, ATM, RIP kinases, PERK), which are known to be deregulated in inflammatory diseases and/or
cancer. New protein-protein interactions that may serve as substrates or regulators of the proteins studied
within our network will be identified and further characterized using innovative proteomics and genomics
approaches. But we also aim at integrating the findings within the consortium in a bioinformatics network to
understand the global functioning and the potential interaction with other signaling, metabolic and disease
networks. Recently the S/T kinases RIPK1 and RIPK3 have been shown to play a crucial role in the
formation of a necrosome complex that signals to necroptosis, but also interacts with bioenergetic
metabolism. How ER-stress and autophagy control cell death and inflammation, and how this leads to DAMP
generation (membrane proteins, intracellular proteins, lipids, cytokines, ATP, etc) and exposure is another
challenging question. The study of necroptotic and ER-stress-induced signaling cascades are two important
topics in this IAP network. These DAMPs could be therapeutically exploited to induce or suppress
inflammatory reactions and will contribute to a better understanding of immunogenic cell death during anticancer
therapies. The cytokines IL-1β and IL-18 are important mediators of inflammation whose transcription
is regulated by NF-B, but which also require posttranslational processing by caspase-1, which is mediated
by signaling complexes called inflammasomes, to become active. We will study cross-talk between NF-B
signaling and the NLRP3 inflammasome as well as its involvement in the development of diabetes in obese
patients and its regulation by unsaturated fatty acids.

Objective 2: Identification of the in vivo role of cell death and inflammation mediators in mouse
models of infectious or sterile inflammatory disease, or cancer models

To study the physiological relevance of our findings, novel transgenic and conditional knock-out/knock-in
mouse lines will be developed (e.g. A20, CYLD, optineurin, NIK, IKK, RIPK1, RIPK3, RIPK4, etc) and
challenged in specific disease models for which the expertise is present within the consortium (e.g. septic
shock, CLP, diabetes, asthma, skin inflammation, liver inflammation, intestinal inflammation, multiple
sclerosis, tumor models, neuronal degeneration, viral encephalitis, M. tuberculosis, etc). Intriguingly,
RIPK1/RIPK3-dependent necroptosis seems a major mediator of in vivo inflammatory reactions, such as
SIRS (systemic inflammatory response syndrome) and intestinal inflammation. Therefore, the involvement of
the RIPK1/RIPK3- signaling pathway in additional in vivo inflammatory models (sepsis, neuronal
degeneration, skin inflammation, asthma, carcinogenesis, diabetes, etc) will be studied. This could result in
new therapeutic strategies to treat inflammation by targeting necroptosis. We will also study the in vivo
contribution of particular caspases (caspase-1, -3, -7) and apoptotic cell death in inflammatory models.

Objective 3: Translational research in order to identify novel potential therapeutic applications to
treat inflammation or cancer.

Several partners are also involved in the development of therapeutic tools that interfere with major
inflammatory mediators such as TNF, IL-33, MMPs (matrix metalloproteinases) or prevent glucocorticoid
receptor inactivation. In addition, members of our network have recently discovered that RIPK1/RIPK3-
dependent necroptosis provides a novel strategy to trigger cell death in apoptosis-resistant cells including
patients’ derived primary tumor samples, thus opening new translational perspectives to exploit necroptosis
as an innovative approach to overcome cancer resistance to apoptosis. Upon identification of novel DAMPS
(objective 1) we will also develop preclinical DAMP(s)-based therapeutic mouse models for the treatment of
inflammation (suppressing DAMPs) or cancer (stimulating DAMPs).

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