Development of novel drug-like small molecule stem cell modulators for cardiomyogenesis and investigation of their mode of action

• Applicant: Professor Dr. Dennis Schade
• Subject Area: Pharmacy
• Term: from 2010 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 172270283

Recent studies of adult cardiac stem/progenitor cells suggest that they are committed to the cardiomyogenic lineage, raising the possibility that these cells might respond to some of the same signals that promote later stages of human embryonic stem cell (hESC)/human induced pluripotent stem cell (hIPSC) cardiomyogenic differentiation, (e.g., when committed progenitors are induced to form cardiomyocytes or other myocardial cell types). We hypothesize that the activation of signaling pathways that control later stages of differentiation in ESC by small molecules can be applied to endogenous regeneration. Development of such compounds is currently hindered by lack of knowledge of the nature of the stem/progenitor cells, the signal transduction pathways and secreted factors that could be used to control their proliferation and differentiation. From a mouse ESC high content screening (HCS), several hit molecules have been identified and were already characterized as late-stage cardiogenic stimulators. These hits will be evaluated as leads for drug candidates to enhance endogenous regeneration and will have to be refined and optimized with respect to potency and drug-likeness to generate promising lead candidates using iterative medicinal chemistry cycles. Optimized leads will also serve as biological tools to investigate SC signaling pathways. Chemical Biology -techniques will be applied to identify cellular targets and shed light on their mode of action, and further HCS performed that will deliver additional hits .

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: John Cashman, Ph.D.; Marc Mercola, Ph.D.