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Organoid SIGNED

Dissecting microbiome and immune interactions in human intestinal (cancer) organoids

Total Cost €

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EC-Contrib. €

0

Partnership

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 Organoid project word cloud

Explore the words cloud of the Organoid project. It provides you a very rough idea of what is the project "Organoid" about.

subjected    cancer    expanded    lgr5    multiple    individual    molecular    trials    effectors    causes    diseased    pioneered    antibodies    imaging    species    reductionist    erc    epithelial    epithelium    manipulation    communities    display    found    organismal    player    activates    intestinal    culture    dissect    agonistic    normal    tils    deep    mechanisms    chart    checkpoint    crc    genetically    ultimately    rests    recombined    patient    apc    infiltrating    colorectal    tumoroids    insights    spondins    adult    transplanted    grow    guts    microbial    exist    describe    mostly    lymphocytes    bacterial    regulators    types    gene    receptors    mini    stem    organoids    clinical    largely    tumor    vitro    microbiome    signals    technologies    cell    crypts    interactions    immune    underlie    healthy    single    crypt    blocking    grant    neutral    sequencing    identification    cultured    perspective    disease    allowed    stable    gut    wnt    leans    ligands    cells    organs    health   

Project "Organoid" data sheet

The following table provides information about the project.

Coordinator
KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW 

Organization address
address: KLOVENIERSBURGWAL 29 HET TRIPPENHUIS
city: AMSTERDAM
postcode: 1011 JV
website: www.knaw.nl

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
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 Coordinator Country Netherlands [NL]
 Total cost 3˙062˙438 €
 EC max contribution 3˙062˙438 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-ADG
 Funding Scheme ERC-ADG
 Starting year 2015
 Duration (year-month-day) from 2015-11-01   to  2020-10-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW NL (AMSTERDAM) coordinator 3˙062˙438.00

Map

 Project objective

We pioneered the essential role of Wnt signals in adult stem cells, i.e. in intestinal crypts. We also found that loss of the APC gene activates the Wnt pathway and causes colorectal cancer (CRC). We then identified a Wnt target gene, Lgr5, which allowed us to define the crypt stem cells. In a previous ERC grant based on these findings, we identified novel Lgr5 stem cells in multiple organs, and defined in vitro culture conditions to grow epithelial organoids from single Lgr5 stem cells. Crucial in this was our identification of the Wnt agonistic R-spondins as the Lgr5 ligands. Cultured 'mini-guts' display all characteristics of normal gut, can be expanded for years, transplanted, and remain genetically stable.

Here, I propose a reductionist, ‘mini-gut’-based approach to two exciting research fields that currently mostly focus at the organismal/patient level: Microbiome research leans on deep-sequencing of complex microbial communities in health and disease; and immune checkpoint research in cancer rests largely on clinical trials of checkpoint-blocking antibodies. While many insights exist into the gut microbiome and -immune system, the epithelium is often treated as a neutral player. ‘Mini-gut’ technology allows us to dissect interactions of the gut microbiome with healthy and diseased epithelium, and of Tumor-Infiltrating Lymphocytes (TILs) with CRC 'mini-guts' (tumoroids).

To this end, we will describe/study 1) All immune receptors, -regulators and -effectors in the individual epithelial cell types. 2) 'Mini-guts' recombined with individual bacterial species, 3) CRC tumoroids recombined with their cultured TILs and subjected to immune checkpoint manipulation. Using advanced molecular and imaging technologies, we will chart the molecular mechanisms that underlie the interactions from the ‘epithelial perspective’. Ultimately, this program will provide molecular detail to the effects of the microbiome and immune system on our gut, in health and disease.

 Publications

year authors and title journal last update
List of publications.
2018 Inha Heo, Devanjali Dutta, Deborah A. Schaefer, Nino Iakobachvili, Benedetta Artegiani, Norman Sachs, Kim E. Boonekamp, Gregory Bowden, Antoni P. A. Hendrickx, Robert J. L. Willems, Peter J. Peters, Michael W. Riggs, Roberta O’Connor, Hans Clevers
Modelling Cryptosporidium infection in human small intestinal and lung organoids
published pages: 814-823, ISSN: 2058-5276, DOI: 10.1038/s41564-018-0177-8
Nature Microbiology 3/7 2019-07-05

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