Die Rolle der Transkriptionsfaktoren HNF3alpha und HNF3beta in der Genregulation von Leber, Pankreas und Hypothalamus

• Antragsteller: Professor Dr. Christian A. Wolfrum
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2001 bis 2004
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5336098

HNF3a and b members of the winged helix nuclear transcription factor family play an important role in liver and pancreas gene regulation. Deletion of the HNF3a gene results in a complex phenotype with early postnatal mortality. HNF3b knock out mice die before birth due to a defect in embryonic development. The project will focus on the biological function of both receptors using two approaches. First, the molecular basis of the HNF3a knock out phenotype will be elucidated. The working hypothesis is that the phenotype observed is due to a genetic dysregulation of either liver, gut, hypothalamus or pancreatic genes. To answer this question, gene expression will be analyzed in these tissues by genechip analysis and identified target genes will subsequently be studied using genetic rescue experiments by preparing transgenic mice overexpressing the identified genes. In addition the identified genes will be used as basis for genetic analysis of patients with type II diabetes of unknown genetic origin. The scientific rationale of the second part will address the molecular basis of HNF3a and HNF3b dependent gene regulation where two hypotheses will be followed, i.e., HNF3a and HNF3b have similar functions, or HNF3a and HNF3b regulate gene expression via different pathways. To answer this question a "knock-in" animal will be prepared which exprexsses HNF3a in the locus of HNF3b to determine whether the first can substitute for the latter. After characterisation of these mice the studies will be extended using in vitro approaches to analyze HNF3-domains that are responsible for cofactor recruitment and which cofactors are bound by the two receptor isoforms. The combination of both approaches will advance our understanding of how HNF3a and b confer their gene regulatory activity and which target genes are regulated in this process.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Kooperationspartner: Professor Dr. Markus Stoffel