H2020Индивидуална стипендия2017–2019

Signalling-in-NODs · Investigation of the role and mechanism of action of NOD2-mediated isoform selective PI3K signalling in gut immunity and inflammation

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

Период: 2017-05-01 → 2019-04-30
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите, чрез които ензимът PI3K и рецепторът NOD2 регулират имунната защита в червата, се анализират чрез проучване на дендритните клетки. Разбирането на тези процеси помага за разработването на нови стратегии за лечение на хронични възпалителни заболявания на червата.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Investigation of the role and mechanism of action of NOD2-mediated isoform selective PI3K signalling in gut immunity and inflammation

Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, is a complex chronic inflammatory condition mainly affecting western societies. Although there has been progress in keeping inflammation down in chronic IBD, each therapy works only in a percentage of patents with variable outcomes. Therefore, there is an unmet need for new therapeutic strategies, which can only be achieved through a better understanding of the molecular mechanisms of host immunity. Phosphoinositide 3-kinases (PI3Ks) are an evolutionarily conserved family of enzymes that generate lipid second messengers and couple to pattern recognition receptors (PRRs) mediating immune responses. Nucleotide oligomerisation domain (NOD)2 is a PRR that detects muramyl dipeptide (MDP) from the bacterial peptidoglycan wall and is the first susceptibility gene identified for Crohn's disease. PI3K inhibitors are important drug targets in cancer and inflammation and are in clinical trials, and yet a major side effect of these therapies is the clinical manifestation of colitis. The host lab previously discovered that a single PI3K isoform, p110δ controls TLR-mediated signalling and impacts gut immunity and inflammation. Specifically, genetic inactivation of the kinase activity of p110δ PI3K in mice results in gut inflammation and colitis. Therefore, we proposed to unravel key control mechanisms by which p110δ conveys host protective functions through PRRs and in special NOD2 pathway and maintains gut immunity and tolerance. The broad aims were to (1) Determine the cell-intrinsic role and mechanism of action of p110δ PI3K orchestrating NOD2 and other PRRs signalling pathways in dendritic cells to induce antimicrobial functions. (2) Discover the role of p110δ PI3K in gut immunity using p110δ PI3K kinase inactivated mice alongside with pharmacological targeting strategies in vivo.

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

Цел на проекта

Inflammatory bowel disease (IBD) is a complex chronic pathology in western societies. There is an unmet need for new therapeutic strategies which can only be achieved through a better understanding of the molecular mechanisms of host immunity. It is established that dysregulated host innate immune recognition either caused by genetic risk variants in pathogen recognition receptor (PRR) molecules or microbial factors is commonly associated with IBD. A unique PRR family member, Nucleotide oligomerization domain (NOD)2 programs gut immunity and protection through autophagy process initiated by the recognition of microbial peptides. Deleterious mutations in NOD2 and autophagy-associated proteins are linked to IBD susceptibility. Despite the advances made in understanding of the mechanisms underlying NOD2 biology, particularly that of autophagy, very little is known about the cell signaling components and their mechanism regulating autophagy under NOD2 pathway. Recently, I discovered that a single Phosphoinositide 3-kinases (PI3K) isoform p110δ is integrated in NOD2 mediated autophagy process. PI3Ks are an evolutionarily conserved family of signaling molecules that integrate PRR signaling. PI3Ks generate lipid second messengers and regulate mediated immune responses. I now propose to unravel key biological phenomenon by which p110δ PI3K convey host protective functions through NOD2-mediated autophagy, ensuring the gut immunity and tolerance. The aims are to (1) Determine the dendritic cell-intrinsic role and mechanism(s) of action of PI3K isoforms in orchestrating anti-inflammatory processes under NOD2-mediated autophagy. (2) Discover the roles of PI3K isoforms in NLR-mediated intestinal immunity using isoform specific PI3K gene-targeted mice alongside with pharmacological targeting strategies in vivo. My plan is integrated with animal models, immunology, cell biology, microbiology and in vivo inflammation studies to elucidate key biological phenomena driving IBD.

Оригинален текст от CORDIS (на английски).

Участници

QUEEN MARY UNIVERSITY OF LONDON · LONDONКоординаторОбединеното кралство