Reactive oxygen species in the epi/pericardium regulate Drosophila heart physio

成人心血管疾病是工业化国家最常见的死亡原因。这个项目的重点是了解心脏的最外层，心外膜，如何关键地调节心肌的发育和功能，因此可能影响心肌病的发展。在心脏发育和功能过程中，心外膜和心肌之间的旁分泌相互作用的确切机制尚不清楚。我们研究的长期目标是通过利用强大的体内果蝇模型系统来确定心外膜和心肌之间诱导信号传导的分子基础。果蝇的心脏是一个由心肌细胞组成的管道，两侧是两排心包细胞（PCs），这是与哺乳动物的心外膜相对应的苍蝇。我们的初步研究表明，pc含有自然发生的，轻微升高的活性氧（ROS）水平，可以调节心肌细胞的功能。这些发现为我们评估ROS在介导心包和心肌之间的旁分泌相互作用中以前未被认识到的作用提供了切入点。初步证据表明，PCs中的ROS和p38通路对心功能的影响相似，这使我们假设PCs中的ROS通过p38信号以非细胞自主的方式调节心脏生理。这一假设将通过追求三个具体目标来验证：(1)表征pc中生理ROS对心脏发育和功能的影响。(2)明确心包ROS下游p38信号在心脏发育和功能中的作用。(3)明确PCs中ROS-p38信号调控心脏生理的分子机制。这些目标将通过基因、生物成像和微阵列实验的结合来解决。该项目有望揭示生理ROS信号如何介导心包和心肌之间的功能相互作用，这对心脏的正常发育和功能至关重要。这些知识将揭示新的疾病机制和心血管疾病的治疗方法。

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.