RE-MYELINATION · Inflammation and de/remyelination coupling in EAE: A focus on the role of soluble TNF and receptors
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-05-01 → 2007-04-30
- EU contribution
- €136,267
- Participants
- 1
- Scheme
- IIF
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Results in brief
Final Activity Report Summary - RE-MYELINATION (Inflammation and de/remyelination coupling in EAE: A focus on the role of soluble TNF and receptors)
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, develops through the immunologic destruction of the myelin sheath of the Central nervous system (CNS). The adult CNS maintains the ability to self-repair by recruiting Neuronal stem and precursor cells (NPCs). When and how this process occurs and why it eventually succumbs to the destructive nature of the disease remain haunting questions in the field. Our detailed histological examination of the inflamed CNS revealed the existence of cellular niches bearing markers spanning all levels of the neural stem cell differentiation pathway. The cytoarchitecture of these niches was reminiscent of the germinal niches, where NPCs resided and supported neurogenesis and gliogenesis throughout adult life. It was therefore possible that what we observed were ectopic niches where NPCs were recruited and received signals to differentiate and become the oligodendrocytes required for tissue repair. Our goal was to identify molecular mechanisms governing such tissue repair. Tumour necrosis factor (TNF) and its receptors, namely p55TNFR and p75TNFR, are known to play a vital role in CNS pathogenesis. More specifically, p75TNFR was implicated in CNS repair and the proliferation of oligodedrocyte precursors. It was noted that p75TNFR-/- animals exhibited exacerbated EAE clinical profile with sustained motor deficits. Interestingly, in the CNS of these animals the numbers of ectopic niches was greatly reduced and the various cellular populations adopted a seemingly random spatial distribution. Real time Polymerase chain reaction (PCR) analysis of the spinal cords of diseased animals revealed the sustained upregulation of the NPC marker nestin in the absence of p75TNFR. Furthermore, we were able to grow neurospheres from the spinal cords of EAE-affected p75TNFR-/- animals but not from wild type littermates. Taken together, our data supported that, in the absence of p75TNFR, the inflamed CNS lacked a properly organised cellular microenvironment and had a sustained pool of undifferentiated NPCs. In summary, our studies shed some light on the role of p75TNFR in the repair of autoimmune demyelination. p75TNFR appeared to have a reparative role through its ability to promote NPC differentiation. We further aimed to elucidate the signalling pathway and the direct or indirect effect of p75TNFR on NPC differentiation. Such knowledge would be invaluable for the advancement of efficient stem cell therapeutic approaches for demyelinating diseases.
Data: CORDIS, © European Union
Project objective
Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system (CNS) that affects more than a million individuals worldwide. The disease develops through the immunologic attack and eventual destruction of the myelin sheath (demyeli nation) that protects neurons of the CNS. The body attempts to repair the ensuing damage through remyelination, which eventually succumbs to the destructive nature of the disease. Our goal is to employ Experimental Autoimmune Encephalomyelitis (EAE), the animal model of MS, to decipher the cellular and molecular events that influence disease processes. Tumour Necrosis Factor (TNF) is one of the immunological components that have proven instrumental for orchestrating the balance of de- and remyelination.We have developed conditional genetic animal models that differentially express soluble TNF (sTNF) vs. transmembrane TNF (tmTNF) and their receptors, p55TNFR vs. p75TNFR, to be exploited for the study of the evolution of EAE. We will specifically investigate how the cell-specific expression and signalling through TNF components affect cellular processes, including oligodendrocyte physiology and immune functions, as well as molecular events, such as signalling cascades, suspected or known to participate in the evolution of EAE. This study will extend our knowledge of the nature of EAE; it will reveal novel biological markers of disease progression and potential targets for its therapy.The project will benefit from the applicant's knowledge of autoimmune diseases a s well as her expertise in a variety of in vitro and in vivo imaging modalities, including confocal microscopy and optical imaging, which will be employed to address the proposed scientific questions. The applicant will be trained in using genetic animal models of neurodegenerative diseases, will extend her knowledge of immuno- and neuro-histopathology and benefit from the transgenic and knockout facilities available at the host institute.
Original text from CORDIS.
Participants
- BIOMEDICAL SCIENCES RESEARCH CENTER ALEXANDER FLEMING"" · VARKIZA, VARICoordinatorCountry levelGreece
Links
Data: CORDIS, © European Union