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CELLPHASE_AD SIGNED

Genetics to understand cellular components of Alzheimer Disease pathogenesis

Total Cost €

EC-Contrib. €

Partnership

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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.

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

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 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.	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

List of publications.
year	authors and title	journal	last update
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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