For most of my career, my research focus has been on early heart development, both normal processes and
dysmorphogenesis leading to cardiac birth defects (see selected citations). For my Ph.D. dissertation research I analyzed the directional movement of pre-cardiomyocytes in the bilateral heart fields to the embryonic midline. I showed a critical involvement of the extracellular adhesion and signaling molecule fibronectin. After setting up my own lab, I continued to study cardiomyocyte cell commitment and differentiation. I demonstrated an important role for the cell adhesion-related and signaling molecule beta-catenin (Linask, 1992). Later beta-catenin was shown to be a key intermediary in the canonical Wnt pathway important in cell fate decisions, cell migration, and cell proliferation in the early development of the cardiovascular and neural systems, bone, and the placenta, among other tissue types.
Subsequently, my lab went on to show that lithium that is used therapeutically for bipolar disorder induces cardiac birth defects by modulating Wnt signaling (Chen et al., 2008). Importantly, we demonstrated that folic acid can prevent the lithium-induced cardiac defects from occurring. Concomitantly, we also showed that folate prevents homocysteine-, as well as alcohol-mediated cardiac defects that are induced at a similar exposure time of early development when the embryo is only three cell layers thick, i.e. gastrulation. The similar misexpression of key Wnt-mediated genes indicates that a commonality of pathways that are affected may exist (Han et al., 2009; Serrano et al, 2010). We are currently following up on studies relating to the underlying mechanisms.
My continuing interest in cell adhesion, the link to the cytoskeleton, and cell signaling led to an analyses of cardiac looping, the process by which the tubular heart bends and loops to form the four-chambered heart. The molecule that we first named flectin, my lab later characterized as being nonmuscle myosin-IIB (NMHC-IIB). A knockout model of NMHC-IIB had already been generated at NIH and was shown to have looping defects. With Dr. Rollins’s engineering group at Case Western using optical coherence microscopy and optical coherence tomography, we were able to analyze one heartbeat in real-time and to define the relationships between the myocardial wall, cardiac jelly, and the endocardium during the looping process (Garita et al., 2011).
While doing the above-described studies, in collaboration with Dr. Jim Huhta, we were the first to adapt the use of
Doppler ultrasound for monitoring mouse embryonic heart function (Gui et al, 1995). Dr. Yonghao Gui, a pediatric cardiologist from Shanghai was involved in these ultrasound studies and his interest in research during his time in my laboratory, led to his eventually starting up a cardiovascular development research program at Shanghai Children’s Hospital. With our continuing collaboration I have had the opportunity to visit his group in Shanghai several times and to have postdoctoral fellows train in my lab. My visits to the Shanghai cardiovascular group have been wonderful experiences. A current collaboration with Dr. Ganesh Acharya on placental blood flow changes and relationship to heart development has led to a visit at the University of Tromsoe in Norway above the Arctic Circle. Several years back I visited Dr. Robert Poelmann’s lab in Leiden, in the Netherlands, to analyze aspects of mechanotransduction mechanisms with Dr. Bernd Hierck. Indeed research and wonderful collaborators have provided multiple opportunities to travel to Japan and European countries to give lectures and to do research. My focus on early cardiomyogenesis, cardiomyocyte specification and differentiation, and the role of folate stabilization of normal cardiomyogenesis provides the foundation for the studies that I will be pursuing in Tartu in relation to human stem cell differentiation and regenerative capabilities. The Fulbright will allow to extend these experiences into a longer time frame with many new collaborations to be initiated at Tartu University!