H2020Индивидуална стипендия2018–2021

COAGULANT · CK2-dependent cytoskeletal regulation and molecular signaling of Neutrophil Extracellular Trap (NET) formation

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-09-01 → 2021-08-31
Финансиране от ЕС: 239 861 €
Участници: 2
Схема: MSCA-IF-GF

Линиите свързват координатора с партньорите.

Накратко на български

Молекулярните пътища, при които неутрофилните клетки отделят мрежи (NETosis), се анализират чрез ролята на ензима PAD4 и NLRP3 инфламозомата. Разбирането на тези процеси помага при разработването на нови методи за лечение на тромбоза и инфаркт.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

CK2-dependent cytoskeletal regulation and molecular signaling of Neutrophil Extracellular Trap (NET) formation

Thrombo-inflammatory diseases such as myocardial infarction, ischemic stroke, and venous thromboembolism, are still a leading cause of morbidity and mortality in the European Union. In the last decade, and even more recently during the ongoing SARS-CoV-2 pandemic, there is a growing body of evidence showing a pivotal role of polymorphonuclear neutrophils and especially Neutrophil Extracellular Trap formation (NETosis) in the development and progression of thrombo-inflammation. Beside its clinical implication, only rudimentary cellular processes and the time course of NETosis could be just recently unraveled, but are still not understood in detail. However, the identification of intracellular molecular pathways and signaling proteins in NETosis is of crucial importance for the development of possible new treatment regimens. The consequent objective of the MSCA was the investigation of molecular signaling pathways which are important for NETosis and which subsequently affect or predict thrombosis in human patients. In this regard, the NLRP3 inflammasome assembly could be defined as pivotal process during NETosis and subsequent venous thrombosis. Moreover, it could be demonstrated that the PAD4 enzyme, which usually regulates NET-associated venous thromboembolism, also affects NLRP3 inflammasome assembly by regulating the protein levels of the most important inflammasome components NLRP3 and ASC. Finally, the obtained findings link the canonical inflammasome signaling and NETosis. This leads to the conclusion that diseases, which are associated with increased PAD4 expression in neutrophils and elevated susceptibility to NETosis, could possibly be linked to elevated NLRP3 inflammasome assembly in both neutrophils and macrophages. Therefore, the PAD-dependent regulation of NLRP3 protein levels could be an important mechanism in inflammasome-driven diseases and makes PADs promising new targets in the therapy of cardiovascular diseases and even opens many new avenues for new approaches in the prevention and treatment of inflammatory diseases.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Platelets play an essential role in hemostasis but are also critically involved in acute arterial thrombotic occlusions leading to myocardial infarction or ischemic stroke and associated tissue fibrosis which are still the major cause of morbidity and disability in the European Union thus causing enormous costs in the health care system.In the last years there is increasing evidence that primary hemostasis and inflammatory atherothrombosis are crucially affected by leukocytes. Thereby the neutrophils represent the most abundant type of immune celly as almost 50% of all leukocytes belong to the neutrophil subset. The neutrophil extracellular trap (NET) formation is mainly know as pro-thrombotic factor in arterial thrombosis and is characterized by release of decondensed chromatin with incorporated histones and neutrophil elastases after neutrophil activation. Beside their pro-thrombotic effect, NETs were also recently described as inducer of tissue fibrosis in vivo thus contributing to cardiac tissue damage. Although tubulin and intermediate filament rearrangements in the cytoskeleton and nuclear envelope are a prerequisite for NET formation and chromatin release, nothing is know about the underlying molecular mechanisms and targets hitherto.Tubulin dynamics and microtubules are known regulators of intermediate filaments in the nuclear envelope thus maintaining the nuclear integrity of cells. Thereby, the ubiquitous Casein kinase 2 (CK2) is an acknowledged upstream molecule of microtubule dynamics and stability in a wide variety of cells. For this reason, the role of the CK2 in microtubule and intermediate filament dynamics during NET formation and its impact on thrombo-occlusive tissue fibrosis in cardiovascular diseases will be investigated resulting in the identification of new molecular structures suitable for improved and personalized treatment of thrombo-occlusive events like myocardial infarction and ischemic stroke.

Оригинален текст от CORDIS (на английски).

Участници

EBERHARD KARLS UNIVERSITAET TUEBINGEN · TuebingenКоординаторГермания
CHILDREN'S HOSPITAL CORPORATION · BostonСъединени щати