H2020Индивидуална стипендия2019–2021

GUTPOLAR · Membrane trafficking as a link between cell polarity and intestinal absorptive function: from C. elegans to mammalian miniguts

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

Период: 2019-05-06 → 2021-05-05
Финансиране от ЕС: 196 708 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Транспортът на мембрани в червните клетки и ролята на комплекса V0-ATPase се изучават чрез модели от червеи и мишки. Това помага за разбирането на механизмите при редки генетични заболявания, които нарушават усвояването на хранителни вещества.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Membrane trafficking as a link between cell polarity and intestinal absorptive function: from C. elegans to mammalian miniguts

Intestinal absorption of nutrients from the diet relies on both the strong polarity of the intestinal epithelial cells and the array of microvilli forming an absorptive brush border (BB) at their apical pole. Previous studies suggested that membrane trafficking plays a major role in the maintenance of the apico-basal polarity in several epithelial models. Since mutations in membrane trafficking factors have been linked to rare genetic disorders affecting the absorptive function of the intestinal epithelial cells, uncovering the molecular mechanisms by which membrane trafficking controls the maintenance of the BB and the polarity in the enterocytes is pivotal in understanding the pathophysiological mechanisms of intestinal absorption diseases and identifying new therapeutic targets. The GUTPOLAR action aimed to better understand how this cellular transport mechanism coordinates the apical localization of polarity and BB components in intestinal cells, notably by focussing on the trans-species function of the V0-ATPase complex, which seems to play a major role in this process. The overall objectives were i) to study the role of the V0-ATPase complex and its genetic partners in polarity and BB maintenance in vivo using the C. elegans intestine as a model and ii) to establish and use mouse intestinal organoids to study the role of the V0-ATPase in polarity maintenance in an advanced mammalian intestine model. Using various genetic and imaging tools in vivo (C. elegans) and ex vivo (intestinal organoids), we demonstrated that the V0-ATPase complex plays a major and conserved role in intestinal BB and polarity maintenance. Notably, we showed that loss of this complex recapitulates the rare genetic absorption disorder Microvillus inclusion disease (MVID) in both models, which paves the way to study its implication in the aetiology of this disease.

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

Цел на проекта

The GUTPOLAR project aims at sustainably reintegrating an Experience Researcher (ER) who will acquire the necessary knowledge and skills to reinforce European research on rare malabsorption diseases.Food absorption relies on the strong polarity of intestinal epithelial cells and the array of microvilli forming a brush border (BB) at their luminal (apical) pole. Some rare genetic malabsorption disorders, characterized by mispolarized PAR polarity modules and BB structural proteins, are caused by mutations in genes coding for membrane traffic factors (i.e. Myo5B in microvillus inclusion disease/MVID). Despite this functional link, little is known about the genetic, physical and functional interactions between membrane traffic, polarity and BB components in vivo and how they control intestinal absorption.The ER uncovered a new role of the V0 sector of the V-ATPase, a complex that controls membrane traffic through organelle acidification, in both polarity and BB components apical polarity maintenance in C. elegans intestine. Most interestingly, V0-ATPase depletion in C. elegans recapitulates the cellular phenotypes observed in patients with MVID, making this complex a very exciting candidate which mechanism, genetic partners and mammalian function need to be characterized. To this end, the ER will first use genetics and super-resolution imaging to study the trafficking routes and the molecular mechanisms controlled by the V0-ATPase in vivo in C. elegans intestine. Then, he will implement mouse intestinal organoids (thanks to a secondment in H. Farin’s lab, Frankfurt, Germany) and use this model to study the conservation of these mechanisms in mammals.Overall, the GUTPOLAR action will allow to describe evolutionary conserved pathways of polarity maintenance and identify some of the mechanisms leading to absorption disorders that may provide the medical community with new therapeutic targets.

Оригинален текст от CORDIS (на английски).

Участници

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция