Projects / Programmes
Aktivacija inflamasoma negativno povratno vpliva na signalne poti odvisne od MyD88 (Slovene)
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
29495 |
PhD Monika Avbelj |
Biotechnology |
Head |
2015 - 2017 |
55 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Significance for science
MyD88 is the central mediator of innate immunity, especially in TLR, IL1R and IL18R signaling and its deficiency leads to strong sensitivity to infection while overexpression leads to the constitutive cell activation. Understanding the regulation of MyD88 is therefore very important for innate as well as the adaptive immune response and for the development of suitable therapeutics. Recently, studies of NLRs gained a lot of attention due to their involvement in diseases from cancer to Alzheimer`s disease. Since TLR activation through MyD88 is a prerequisite for NLR activation, we believe that discovery of a new mechanism of regulation of the key player MyD88 in innate immune response will have a strong impact on the understanding of the connections between signaling mediated by TLRs and NLRs, the role of MyD88 and caspase1 in inflammation and for the potential therapeutic interventions. Furthermore, besides discovering a new regulatory mechanism of inter-receptor signaling, an additional signaling role for MyD88 was also published. We showed that the N-terminal domain of MyD88 composed of apparently unstructured 21 amino-acid residues is involved in localization and clustering of MyD88 and is required for the efficient signaling. Furthermore, we found that the N-terminal peptide of MyD88 interacts with phosphatidic acid, which potentiates MyD88-mediated signaling through TLRs. Results thus provide new insight into the mechanism of MyD88 mediated signaling. While the membrane anchoring of MyD88 augmented a response to TLR activation, regulation of the association of MyD88 to the membrane, e.g. via phosphatidic acid turnover might provide an additional layer of fine tuning of the immune response. Further identification of this mechanism could represent a pharmacological target to either suppress the excessive inflammation or augment activation in case of vaccine or cancer immunotherapy. Our work is important for the fundamental development of innate immunity field since novel functions of MyD88 were discovered (MyD88 as a target for caspase-1 in negative regulatory mechanism involving TLR/NLR signaling and as a binding partner for phosphatidic acid enabling an additional level of fine-tuning of the immune response) as well as unraveling new possibilities for therapeutics interventions.
Significance for the country
Discovery of a new negative feedback mechanism of crosstalk between NLR and TLR receptors will open a new area for basic research and possible development of therapeutics. Cleavage of MyD88 might represent a new biomarker that could be useful in diagnostics of inflammatory disease. This discovery may lead to the development of the clinical test that could detect the cleaved MyD88 and gives Slovene biopharmaceutical companies possibilities for collaboration on the applicative projects. Furthermore, during our project we also collaborated with Clinical Centre in Ljubljana and Medical Faculty in Maribor. This collaboration enables both parties to exchange their expertise and knowledge leading to increased quality in research and publications thus creating attracting research environment in Slovenia for foreign researchers.
Most important scientific results
Annual report
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2015,
final report
