Seminar organisé par Eric N. Olson du 28 septembre au 03 octobre 2009.
Isabelle Baro, Margaret Buckingham, Vincent M. Cristoffels, Robert Kelly, Issei Komuro, Marek Michalak, Mona Nemer (organisateur), Eric N. Olson (organisateur), Nadia Rosenthal, Jay W. Schneider, Robert J. Schwartz, Didier Stainier, Eva Van Rooij, Deborah Yelon, Katherine Yutzey, Stéphane Zaffran
A meeting entitled “Advances in Heart Development: From Molecules to Cures” was held at the Fondation des Treilles on September 28 – October 3, 2009. This meeting brought together international leaders in a range of areas of cardiovascular biology. The meeting was lively and interactive, accompanied by in-depth discussions of current scientific issues and future therapeutic applications. The social interactions, scenic venue, and incredible French cuisine made for a very special experience.
The meeting began with lectures on cardiovascular development by Didier Stainier (UCSF), Margaret Buckingham (Pasteur Institut), Robert Kelly (Marseilles) and Mona Nemer (University of Ottawa). Dr. Stainier showed spectacular images of cardiovascular development in zebrafish. Of particular interest were several new imaging technologies that allowed for visualization of cardiac conduction and contractility in real-time, making possible to pin-point the precise cluster of cells responsible for the function of the pacemaker. Dr. Buckingham discussed new ideas on the embryonic origins of cells from the heart and head muscle lineages, presenting evidence for shared progenitor cells for these different muscle cell types. Robert Kelly next discussed work on origins of cardiac lineages in the mouse, as well as mechanisms for myocardial regeneration from the epicardium. Mona Nemer focused on the functions of TBX and GATA transcription factors in cardiac development. She presented very exciting new findings on the role of nitric oxide synthesis (NOS) in the control of endocardial development downstream of GATA and TBX. Dr. Nemer also presented new results on the functions of GATA5 as a regulator of cardiovascular development, the loss of which results in congenital valve defects.
In the second session, mechanisms of gene regulatory control during cardiogenesis were discussed. Marek Michalak(University of Alberta) showed interesting studies on calreticulum, a component of the sarcoplasm reticulum that regulates calcium signaling and calcineurin activity in the heart. Robert Schwartz (Houston) showed data on the role of the SUMO modification in cardiogenesis. This work revealed antagonistic functions of SUMO-1 and SENP in cardiogenesis. This work promises to open an entire new area of cardiovascular biology through the eventual identification of specific protein substrates of Sumoylation and in the elucidation of their mechanisms of action.
MicroRNAs have recently emerged as powerful regulators of cardiovascular biology. Dr. Eric Olson (Dallas) presented recent studies on several microRNAs that mediate stress signaling in striated muscles. He discussed a network of microRNAs encoded by myosin genes that control pathologic cardiac hypertrophy and myofiber identity. In addition, microRNAs involved in vascular stenosis and muscle atrophy during ALS were discussed. Dr. Eva van Rooij (Boulder, Colorado) then presented a perspective on the development of microRNAs as therapeutic targets for drug development. She discussed new findings on chemical modifications of oligonucleotides that facilitate inhibition of microRNAs (anti-mirs) or elevation of microRNAs (miR mimics). These sorts of microRNA therapeutics have already shown efficacy in a number of models of cardiovascular disorders.
The next session focused on abnormalities and the cardiac conduction system leading to arrhythmias and channelopathies. Isabelle Baro (Nantes) presented an outstanding overview of the functions of ion channels in cardiomyocytes and their disruption in disease. Vincent Christoffels (Amsterdam) presented studies on the origin and development of the cardiac conduction system, also focusing on gene regulatory mechanisms including T-box proteins that control the expression of cardiac ion channels. Another session on cardiovascular disease and new therapeutic approaches was accompanied by talks on a number of model organisms. Debbie Yelon (UCSD) presented interesting new data on cardiac progenitor pools in zebrafish that govern growth and development of the heart. Issei Komuro (Kyoto) presented work on the Wnt signaling pathway and its role in regulating cardiomyocyte differentiation and cardiac remodeling. Katherine Yutzey (Cincinnati) addressed valve development and important new data on the molecules and pathways underlying normal valve formation and function. Overall, these sessions highlighted the knowledge gap and pointed to new pathways that could be therapeutic targeted for cardiac repair and regulation.
In an especially lively session, Nadia Rosenthal (Rome) discussed new strategies for enhancing cardiac regeneration. Her work focused on the IGF-1 signaling pathway and its remarkable ability to promote repair of the heart and other muscle tissues. Jay Schneider (Dallas) presented state of the art results on a collection of small drug-like molecules capable of promoting cardiac gene expression and inhibiting fibrosis in the heart following myocardial injury. These cardiogenic molecules (isoxozoles) appear to act on a unique population of epicardial derived progenitor cells and offer great promise as future therapeutics for enhancing cardiac function in the setting of disease.
Overall, this was a timely meeting that brought together outstanding investigators working on complementary topics of high interest in the field of cardiovascular biology. Interactions among the group led to exciting discussions and new perspectives on translating basic discoveries and basic science toward the eventual development of novel therapeutics. A significant number of cross-Atlantic collaboration will develop as a direct result of the meeting.