The Simon laboratory has a longstanding interest in organ development during embryogenesis and regenerative repair of tissues during adult stages, with an emphasis on the heart and the limbs. This zebrafish embryo displays the heart (a = atrium and v = ventricle, green fluorescence) and tail vasculature (red fluorescence). Our research generates a deeper understanding of the gene and protein functions during these important biological processes, promising the identification of new therapeutic targets for disease intervention and improved clinical care.
Current Research Projects
Skeletal and Cardiac Muscle Regeneration
Unlike humans, newts and zebrafish can regenerate many injured tissues and lost appendages without scar formation. Employing these regeneration-competent species, we are investigating the underlying mechanisms that control the differentiated state of the cell and regulate regenerative processes. Studying skeletal and cardiac regeneration, my laboratory demonstrated that in addition to cell-internal proteins, e.g. transcription factors, an extensive and dynamic remodeling of the extracellular matrix (ECM) at the wound site is critical for tissue regeneration. Using a cross-disciplinary approach incorporating developmental biology, cell signaling, and material sciences, we are now exploring the possibility to mimic the complex regeneration-stimulating ECM conditions found in vivo in more simplified in vitro culture systems using synthetic biomaterials. The longterm goal of this research is to develop new opportunities for the enhancement of regenerative responses in humans with an emphasis on the heart and the limbs. Our research provides a deeper understanding of the respective gene and protein functions during these important biological processes, promising the identification of new therapeutic targets for disease intervention and improved clinical care.
Cardiac Valve Formation and Disease Mechanisms
Mutations in Tbx transcription factors are known to cause serious cardiac and limb malformations in humans, e.g. Holt-Oram syndrome, ulnar-mammary syndrome. We have identified the actin-binding protein Pdlim7 to localize Tbx4 and Tbx5 proteins at the cytoskeleton and in this way control the availability of the transcriptions factors in the nucleus to activate target genes. In zebrafish and mouse models we reported that misregulation of Pdlim7 results in heart defects, especially malformations of the cardiac valves. More recently, my laboratory made the fascinating discovery that the inactivation of the Pdlim7 protein in the mouse causes spontaneous excessive vascular blood clots, resulting in significant early lethality. Thus, these Pdlim7-deficient mice provide a unique opportunity to better understand the causes and possible treatments of hyper-coagulopathies. Particularly, our research shines light on a yet unknown Pdlim7-Arf6 regulatory axis controlling actin dynamics in platelets. This work has the potential to identify new promising therapeutic targets for the regulation of blood clot formation in humans.
Model Organisms and Methodologies
To address questions in congenital cardiovascular conditions and regenerative repair we are employing complementary vertebrate model systems. For our developmental studies, we are using the chicken which allows direct manipulation of the embryo in ovo; the zebrafish because the small and transparent embryos facilitate live imaging of the developing organism’s organs and cells; and the mouse because of superior technologies available for genetic manipulation. For our regeneration studies, we take advantage of the unique ability of adult zebrafish and newts, as these species can regenerate complete limbs and heart ventricular muscle throughout their lifetimes.
In order to understand the underpinning functional mechanisms at the organismal, cellular, and molecular level, the laboratory is using a range of molecular, biochemical, cell biological, and genetic techniques to engineer genes and proteins for functional testing in vivo and in vitro.