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。该项目的重点是了解心脏的最外层，心外膜，如何严格调节心肌发育和功能，因此可能会影响心肌病的发展。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知之甚少。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的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状结构，两侧是两排心包细胞（PC），它们与哺乳动物的心外膜相对应。我们的初步研究表明，PC含有天然存在的，略高水平的活性氧（ROS），可以调节心肌细胞的功能。这些发现为我们评估ROS在介导心包和心肌间的旁分泌相互作用中以前未被认识的作用提供了一个切入点。初步证据表明，ROS和p38通路在PC发挥类似的影响，对心脏功能，使我们假设，ROS在PC的作用，通过p38信号转导，以非细胞自主的方式来调节心脏生理。这一假设将通过追求三个具体目标来检验：（1）表征PC中生理性ROS对心脏发育和功能的影响。(2)明确心包ROS下游p38信号对心脏发育和功能的作用。(3)定义PC中ROS-p38信号转导调节心脏生理学的分子机制。这些目标将通过遗传、生物成像和微阵列实验的结合来实现。该项目有望揭示生理ROS信号传导如何介导心包和心肌之间的功能相互作用的新见解，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.