H2020Индивидуална стипендия2016–2018

WntTraffic · Characterising the spatial organisation and regulation of the Wnt receptor complex in stem cells and cancer

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

Период: 2016-04-01 → 2018-03-31
Финансиране от ЕС: 177 599 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Рецепторът Lgr5 в стволовите клетки на червата се проследява, за да се разбере как се движи и взаимодейства с други молекули. Това помага за разбирането на развитието на рака и създаването на по-точни стратегии за борба с него.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Characterising the spatial organisation and regulation of the Wnt receptor complex in stem cells and cancer

The small intestine epithelium is one of the most proliferative tissues in the human body, renewing every 3-5 days. The rapid turnover is sustained by stem cells under the control of Wnt signalling, dictating critical cell behaviours during both embryonic development and adult tissue homeostasis. Deregulation of this pathway is linked to a plethora of diseases including tumorigenesis. Leucine rich repeat G–protein coupled receptor 5 (Lgr5) is a Wnt pathway receptor that serves as a molecular determinant of stem cells with its ligand R-spondin (RSPO). Despite its importance as a marker for this critical niche, little is known about Lgr5 trafficking and it’s signalling which may be intimately linked. This information is crucial to understand how stem cells perceive and respond to their environment and ultimately for developing specific and successful anticancer strategies. The key objective of this project was to resolve early critical molecular details that drive Wnt signalling in stem and cancer cells. Utilizing a novel tool, SNAP-tagged Lgr5, we were able to exclusively track the cell membrane subpopulation of the Lgr5 from early molecular events that occur immediately after receptor activation such as endocytosis through to late events such as lysosomal degradation. These experiments led to formulation of a trafficking model of Lgr5 in an unbound and a ligand-bound state. Moreover, insights into interactions with Wnt signalling players, such as RNF43 and Wnt receptor complex components, have been gained. Future studies based on our findings will help detailed characterization of the stem cell marker Lgr5 and may provide further understanding of the molecular mechanism of Lgr5-RSPO-induced Wnt pathway activation in stem cells and cancer.

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

Цел на проекта

Wnts are a family of secreted glycoproteins that control maintenance and proliferation of stem cell reservoirs during tissue homeostasis and regeneration after injury. Deregulated Wnt signalling due to mutations in important signalling intermediates is strongly linked to disease. The complex molecular mechanisms mediating Wnt-induced cell responses are therefore of wide interest and the underlying protein interactions provide attractive drug targets, particularly in regenerative medicine and cancer treatment. The earliest events that occur after Wnts bind their receptors at the cell surface, such as receptor endocytosis and recruitment of cytoplasmic effectors, are decisive for downstream gene activation but the underlying mechanisms by which these events process and tune the Wnt signal remain poorly understood. The key objective of this proposal is to resolve critical molecular events that drive initiation of the Wnt cascade in stem and cancer cells. By using a novel tool developed in the Maurice laboratory to detect endogenous Wnt-bound complexes, The Applicant will focus on the following central objectives: 1. To elucidate Wnt receptor localisation in sub-cellular compartments2. To examine the regulation of Wnt receptor trafficking and turnover in response to Wnt signalling3. To investigate how cancer cells exploit Wnt receptor trafficking to drive tumour growthTo meet these objectives, The Applicant will be trained to employ an integrated approach combining biochemistry and genome editing in intestinal organoid cultures with advanced imaging including immuno-electron microscopy to develop a unique set of tools to study Wnt receptor trafficking and turnover at the endogenous level. The expected insights will be vital to understand how pathway activation is controlled and for strategies to interfere with Wnt signalling in disease.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITAIR MEDISCH CENTRUM UTRECHT · UtrechtКоординаторНидерландия