Projektbeschreibung
Neuartige genetische Strategie ebnet den Weg für moderne Zellbeobachtungen
Insulinproduzierende Betazellen werden aus bipotenten Vorläuferzellen im primitiven duktalen Pankreasepithel gewonnen. Die für diese Differenzierung verantwortlichen zellulären Mechanismen wurden bisher jedoch noch nicht eingehend untersucht. Ein am EU-finanzierten Projekt MADMpancreas beteiligtes Forschungsteam hat kürzlich entdeckt, dass die Betacellulin-spezifische Signalgebung des epidermalen Wachstumsfaktor-Rezeptors (Epidermal Growth Factor Receptor, EGF-Rezeptor) gleichzeitig die apikobasale Polarität und die transkriptionelle Festlegung auf das endokrine Schicksal moduliert, was zur Betazelldifferenzierung führt. Daher möchte das Projekt in erster Linie die Rolle des EGF-Rezeptors bei der Betazelldifferenzierung erforschen, wobei gleichzeitig das individuelle Zellverhalten in der sich entwickelnden Bauchspeicheldrüse in situ beobachtet werden soll. Das Forschungsteam bedient sich der innovativen mausgenetischen MADM-Strategie (Mosaic Analysis with Double Markers), um den Spiegel des EGF-Rezeptors in bipotenten Vorläuferzellen quantitativ zu manipulieren und veränderte Zellen zu kennzeichnen.
Ziel
Insulin producing beta cells are derived from bipotent pancreatic progenitors (bi-PPs) that constitute the primitive ductal epithelium. While we now know a great deal about the transcriptional networks required for endocrinogenesis and commitment to the beta lineage, considerably less is understood about the cellular events that initiate delamination and activate differentiation networks. The host group recently found that ligand-specific Egfr signaling is essential for these processes. Signaling by the highly potent Egfr ligand betacellulin diminishes apicobasal polarity leading to upregulation of Ngn3, delamination, and beta cell differentiation. The overall aim of this proposal is to elucidate the role of Egfr signaling in the beta cell differentiation process. I will ask: Is the seemingly stochastic differentiation of bi-PPs regulated by inherent differential Egfr signaling? Do quantitative differences in this single pathway lead to different cellular outcomes? How does the targeted loss of Egfr in Ngn3-expressing endocrine precursors affect their differentiation? What are the genes regulated by Egfr pathway activation that putatively commit Ngn3+ progenitors to a beta cell fate? And how does the disruption of endocrine differentiation affect ductal morphogenesis? Answers to these questions have remained elusive because of the difficulty of observing individual cell behaviors in situ in the developing pancreas. To meet this challenge, I will adapt the cutting edge mouse genetic tool Mosaic Analysis with Double Markers (MADM) to quantitatively manipulate Egfr levels in bi-PPs and to concomitantly label altered cells. The successful implementation of MADMouse will deliver findings of immediate interest to investigators seeking to improve the directed differentiation of therapeutic grade beta cells from hPSCs. I will augment my expertise in precision mouse genetics with training in hESC culture enhancing my career goal of establishing my own research group.
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MSCA-IF-EF-ST - Standard EFKoordinator
1165 Kobenhavn
Dänemark