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

外膜/心包中的活性氧调节果蝇心脏生理

• 批准号: 8625781
• 负责人: Hui-Ying Lim
• 金额: $ 32.76万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8625781
• 关键词: Address; Adopted; Adult; Affect; Antioxidants; Biological Models; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cells; Data; Development; Developmental Biology; Disease; Drosophila genus; Epicardium; Fluorescence-Activated Cell Sorting; Future; Gene Targeting; Genes; Genetic; Goals; Health; Heart; Homeostasis; Image; Instruction; Knowledge; Label; Life Cycle Stages; MAPK14 gene; Mediating; Microarray Analysis; Modeling; Molecular; Mutation; Myocardial; Myocardium; Oklahoma; Pathway interactions; Pericardial body location; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Physiology; Property; Protein Kinase; Reactive Oxygen Species; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Surface; System; Testing; Therapeutic; Therapeutic Intervention; Tube; Work; base; cardiogenesis; cellular imaging; fly; genetic manipulation; heart function; human disease; in vivo; insight; novel; paracrine; pericardial sac; postnatal; research study; upstream kinase

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.

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）如何严格调节心肌的发育和功能，因此可能影响心肌病的发展。人们对心脏发育和功能过程中心外膜和心肌之间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定义心外膜和心肌之间感应信号传导的分子基础。果蝇心脏是一个由心肌细胞组成的管子，两侧是两排心包细胞（PC），它们是果蝇中哺乳动物心外膜的对应物。我们的初步研究表明，PC 含有天然存在的、稍微升高水平的活性氧 (ROS)，可以调节心肌细胞的功能。这些发现为我们评估 ROS 在介导心包和心肌之间的旁分泌相互作用中的先前未被认识的作用提供了切入点。初步证据表明，PC 中的 ROS 和 p38 通路对心脏功能具有相似的影响，因此我们推测 PC 中的 ROS 通过 p38 信号传导以非细胞自主方式调节心脏生理机能。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 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 信号传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。该项目预计将揭示生理 ROS 信号如何介导心包和心肌之间功能相互作用的新见解，这对于心脏的正常发育和功能至关重要。这些知识将揭示心血管疾病的新疾病机制和治疗方法。