Kühl lab - research
Heart development (Kühl M)
The heart is the first functional organ during mammalian development. Defects in the development of cardiac tissue result in congenital heart diseases, which occur in approximately 1% of all newborns and are estimated to be the cause of 10% of still-births and spontaneous abortions. Defects in regulatory molecules that act early in heart development have been linked to congenital cardiovascular malformation. A detailed analysis of normal heart development at the molecular level will deepen our understanding of pathological changes in congenital heart diseases. Furthermore, the recent identification of adult cardiac stem cells that can differentiate into functional cardiomyocytes opens a new perspective in the therapy of heart diseases in the long run and reinforces the necessity to understand the process of normal cardiac development. We recently have shown that certain Wnt signalling activities are required for vertebrate cardiac development (Pandur et al., Nature 2002; Gessert at al. Dev. Biol. 2008; Gessert and Kühl, Dev. Biol. 2010; Dorn et al. Stem Cells 2015 ). Currently our studies focus on the characterization of gene regulatory networks and extra cellular growth factors during cardiac development.
Neural development (Kühl SJ)
During neural development, non-canonical Wnt signalling pathways regulate the expression of selected targeted genes (Maurus et al., EMBO J. 2005). Target genes of non-canonical Wnt are among others Pescadillo, Peter Pan and Alcam (Gessert ert al., Dev. Biol. 2007; Bugner et al. Development 2011; Cizelsky et al., Development 2013). In this context, we are currently further investigating the molecular mechanisms underlying non-canonical Wnt during neural development in the vertebrate organism Xenopus laevis. Moreover, we are interested in the mechanisms underlying neurodevelopmental disorders in humans. In collaboration with clinical reseachers, we therefore examine the function of potential candidate genes involved in neurodevelopmental processes during early neural development in the Xenopus leavis embryo (Hempel et al., J. Med. Genet. 2016).
Systems Biology of Aging (Kühl M)
Members of the Wnt family of extracellular ligands can activate different intracellular signaling branches that are highly connected and interdependent to form a complex signaling network (Kestler and Kühl, 2008). Several target genes of Wnt signaling regulate Wnt signaling in a negative feedback loop. Taken together this allows for a switch-like or an oscillatory behavior of pathway activity under certain conditions (Wawra et al., 2007; Kestler et al. 2011). This complexity hampers an intuitive understanding of the global behavior of this network in a given cellular context. Changes in Wnt as well as Insulin like Growth Factor 1 (IGF1) signaling have been shown to be associated or even causal for different aspects of aging such as senescence or stem cell aging. We have recently found that intestinal stem cells (ISCs) with high Wnt activity are more prone to DNA damage in comparison to Wnt low ISCs in the aging model of telomerase deficient mice (Terc-/-), resulting in p53 mediated apoptosis (Tao et al., 2015). Mathematical models contribute to our understanding of complex signal transduction circuits and gene regulatory networks and furthermore help to identify causal relationships for changes in signaling in diseases and during aging (Kestler et al. 2008). This a collaboration project with the Institute of Medical Systems Biology (Head: Prof. Dr. Hans Kestler).