Adult cardiovascular disease is the most common cause of death in the industrialized world. This project focuses on understanding how the outermost layer of the heart, the epicardium, critically regulates myocardial development and function, and is therefore likely to influence the development of cardiomyopathies. The precise mechanisms underlying the paracrine interactions between the epicardium and the myocardium during heart development and function are poorly understood. The long-term goal of our studies is to define the molecular basis for the inductive signaling between the epicardium and myocardium, by exploiting the powerful, in vivo Drosophila model system. The Drosophila heart is a tube comprising myocardial cells flanked by two rows of pericardial cells (PCs), which are the fly counterpart to the mammalian epicardium. Our preliminary studies revealed that PCs contain naturally occurring, slightly elevated levels of reactive oxygen species (ROS) that could modulate the function of the cardiomyocytes. These discoveries serve as an entry point for us to assess a previously unrecognized role of ROS in mediating the paracrine interaction between the pericardium and myocardium. Preliminary evidence indicates that ROS and the p38 pathway in PCs exert similar effects on cardiac function, leading us to hypothesize that ROS in PCs act through p38 signaling to regulate cardiac physiology in a non-cell autonomous manner. This hypothesis will be tested by pursuing three specific aims: (1) Characterize the effects of physiological ROS in PCs on heart development and function. (2) Define the roles of p38 signaling downstream of pericardial ROS on cardiac development and function. (3) Define the molecular mechanisms by which ROS-p38 signaling in PCs modulates cardiac physiology.
These aims will be addressed by a combination of genetic, bio-imaging and microarray experiments. This project is expected to reveal novel insights into how physiological ROS signaling mediates the functional interactions between the pericardium and myocardium, which are essential for proper heart development and function. This knowledge will uncover new disease mechanisms and therapeutic approaches for cardiovascular diseases.
The proposed studies will not only allow us to elucidate the basic molecular mechanisms that regulate the interactions between the epi/pericardium and myocardium, which are essential for proper heart development and homeostasis, but also provide general insights into the composition and function of physiological ROS signaling. Such insights can be further explored in the mammalian system that may facilitate the therapeutic interventions of relevant human diseases, including cardiovascular diseases.
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