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CELLPHASE_AD SIGNED

Genetics to understand cellular components of Alzheimer Disease pathogenesis

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 CELLPHASE_AD project word cloud

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

mice    validating    versatile    putative    time    genomic    worldwide    phenotypes    chimeric    pathology    tau    dynamic    pathogenesis    neuron    brain    possibilities    population    600    vitro    wild    answer    centric    human    transplanted    explore    polygenic    inflammation    mouse    context    cholesterol    accelerated    progression    influences    rodent    arm    extensive    transcriptomics    genetics    crisper    followed    linked    capture    translation    view    expression    platform    bioinformatics    beta    models    inducible    mechanistic    microglia    risk    health    scores    pathological    cell    limitations    hypotheses    gt    humanized    lines    astroglia    cells    single    vivo    alzheimer    patient    engineered    cas9    establishes    profiles    disease    insights    largely    patients    ad    manipulate    generate    ips    genes    therapies    drug    complexity    genetic    axis    understudied    expressed    isogenic    makeup    provides    classically    first    validate    stem   

Project "CELLPHASE_AD" data sheet

The following table provides information about the project.

Coordinator
VIB 

Organization address
address: RIJVISSCHESTRAAT 120
city: ZWIJNAARDE - GENT
postcode: 9052
website: www.vib.be

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Belgium [BE]
 Total cost 2˙374˙997 €
 EC max contribution 2˙374˙997 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2018-ADG
 Funding Scheme ERC-ADG
 Starting year 2019
 Duration (year-month-day) from 2019-11-01   to  2024-10-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    VIB BE (ZWIJNAARDE - GENT) coordinator 2˙374˙997.00

Map

 Project objective

Alzheimer disease (AD) is a major health problem worldwide. New therapies require an accelerated translation of genetic information into mechanistic insights. Given limitations of rodent models, fully humanized models are needed to capture the complexity of the disease process. Human stem cells (iPS) provide great possibilities but are largely investigated in vitro with associated limitations. Many of the novel genetic risk factors for AD are expressed in microglia and astroglia, which remains an understudied population in this classically neuron-centric field. We propose here mouse-human chimeric mouse models to test the effects of AD-associated genetic risk factors on the phenotypes of transplanted microglia and astroglia derived from patients and from genomic engineered, isogenic stem cells. The cells will be followed during disease progression in brain of wild type and of mice developing Aβ- and Tau- pathology. Using single cell transcriptomics, a dynamic view of the cell states over time is generated. In a first arm of the project, we investigate how the genetic makeup of patient derived stem cells with high and low polygenic risk scores influences pathological cell states. In the second arm of the project, we generate inducible Crisper/CAS9 iPS isogenic cell lines to manipulate rapidly and specifically the expression of 4 selected AD associated genes linked to a putative cholesterol pathway but also affecting inflammation. These cell lines will be used also in the second phase of the project when validating hypotheses generated from the extensive bioinformatics analysis of the 600.000 single human cell profiles generated. We expect to identify and validate >5 novel drug targets in the astroglia-microglia axis of AD pathogenesis. Our work provides humanized models for AD, an answer on how genetic makeup affects microglia and astroglia in an AD relevant context, and establishes a highly versatile platform to explore human genetics in human cells in vivo.

 Publications

year authors and title journal last update
List of publications.
2019 Renzo Mancuso, Johanna Van Den Daele, Nicola Fattorelli, Leen Wolfs, Sriram Balusu, Oliver Burton, Adrian Liston, Annerieke Sierksma, Yannick Fourne, Suresh Poovathingal, Amaia Arranz-Mendiguren, Carlo Sala Frigerio, Christel Claes, Lutgarde Serneels, Tom Theys, V. Hugh Perry, Catherine Verfaillie, Mark Fiers, Bart De Strooper
Stem-cell-derived human microglia transplanted in mouse brain to study human disease
published pages: 2111-2116, ISSN: 1097-6256, DOI: 10.1038/s41593-019-0525-x
Nature Neuroscience 22/12 2019-12-16

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