Investigating the pathogenic mechanisms underlying TUBB2B-related brain malformations using induced pluripotent stem cells and cerebral organoids.

Projektinformationen

MiniBRAIN

ID Finanzhilfevereinbarung: 800247

DOI 10.3030/800247

Projekt abgeschlossen

EK-Unterschriftsdatum 19 März 2018

Startdatum 1 März 2019

Enddatum 28 Februar 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten € 166 156,80

EU-Beitrag € 166 156,80

Koordiniert durch

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Austria

Ziel

Mutations in TUBB2B are associated with a range of malformations of cortical development: severe structural brain disorders stemming from abnormal cerebral cortex formation. Functional investigation of TUBB2B mutations will enable us to elucidate distinct pathogenic mechanisms underlying various malformations and advance our understanding of normal brain development.
TUBB2B is highly expressed during embryonic brain development. It encodes a major component of microtubules (MTs), which perform essential roles during neuronal proliferation, neuronal migration and cortical organisation. I have obtained preliminary data in non-neuronal cells that suggests certain (but not all) TUBB2B-related malformations result from impaired cell division during neurogenesis. This highlights a potential disease-specific mechanism. I will investigate this hypothesis using state-of-the-art induced pluripotent stem cells (iPSCs) and cerebral organoid (COs) technologies, more relevant to brain development.
I will generate iPSCs from fibroblasts obtained from patients with specific TUBB2B genotypes and brain phenotypes. I will use CRISPR/Cas9 genome editing to generate isogenic controls (in addition to a generic wild type line). Mutant and control iPSCs will be differentiated into a neural lineage to study effects of mutations on cell cycle and MT dynamics. Subsequently, differentiated cells will be aggregated into COs; self-organising ‘mini-brains’ that recapitulate human brain development and disease. I will employ immunohistochemistry and microscopy to examine TUBB2B mutation effects on neuronal proliferation, migration and organisation.
I will hosted by Dr David Keays (IMP, Vienna). His lab are global leaders in tubulin-gene research and work in close collaboration with the pioneers in CO techniques (Knoblich Lab, IMBA, Vienna). Dissemination and communication of results will impact the scientific community, promote EU-based research and establish me as a reputable figure in the field.

Wissenschaftliches Gebiet

• medical and health sciences › medical biotechnology › genetic engineering › gene therapy
• natural sciences › physical sciences › optics › microscopy
• medical and health sciences › medical biotechnology › cells technologies › stem cells
• natural sciences › biological sciences › genetics › mutation
• natural sciences › biological sciences › genetics › genomes

Programm/Programme

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility

Thema/Themen

• MSCA-IF-2017 - Individual Fellowships

Aufforderung zur Vorschlagseinreichung

H2020-MSCA-IF-2017

Finanzierungsplan

MSCA-IF-EF-ST - Standard EF

Koordinator

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

• Netto-EU-Beitrag: € 166 156,80
• Adresse: CAMPUS-VIENNA-BIOCENTER 1 ; 1030 Wien ; Österreich
• Region: Ostösterreich › Wien › Wien
• Aktivitätstyp: Private for-profit entities (excluding Higher or Secondary Education Establishments)
• Gesamtkosten: € 166 156,80