ROS signaling, intercellular communication and heart development and function

ROS 信号传导、细胞间通讯以及心脏发育和功能

• 批准号: 9322803
• 负责人: Hui-Ying Lim
• 金额: $ 42.88万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322803
• 关键词: Address; Affect; Area; Arrhythmia; Biological Models; Candidate Disease Gene; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cell membrane; Cells; Coupled; Data; Development; Disease; Dissection; Drosophila genus; Electron Transport; Embryo; Generations; Genes; Genetic; Genetic Epistasis; Heart; Heart Abnormalities; Heart Diseases; Heart failure; Human; Ion Channel Protein; Knowledge; Life Cycle Stages; MAP Kinase Gene; MAPK14 gene; Mammals; Mediating; Mitochondria; Molecular; Mutation; Myocardial; Myocardial dysfunction; Myocardium; NADPH Oxidase; Paracrine Communication; Pathway interactions; Pericardial body location; Phenocopy; Physiological; Play; Procedures; Proteins; Publishing; RNA Interference; Reactive Oxygen Species; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Septate; Signal Pathway; Signal Transduction; Source; Staging; TRPA channel; Testing; Tube; Work; abstracting; base; bioimaging; cardiogenesis; differential expression; fly; genetic manipulation; heart function; improved; insight; intercellular communication; novel; paracrine; peroxisome; public health relevance; research study; sudden cardiac death; transcriptome sequencing

DESCRIPTION (provided by applicant): Abstract The central aim of the proposed research is to define a novel signaling mechanism of reactive oxygen species (ROS) in mediating the interaction between cardiac myocytes and nonmyocytes which is essential for proper heart development and function, using the fruit fly Drosophila as a model system. Perturbations of the intercellular communication between cardiac myocytes and nonmyocytes are a major source of cardiac arrhythmias, sudden cardiac death and heart failure. A better understanding of the functional interactions between cardiac myocytes and nonmyocytes is therefore necessary for the development of new and improved therapies for human heart diseases. The fruit fly heart serves as an efficient model system for elucidating the precise molecular basis of cardiac myocyte-nonmyocyte functional interactions. The fly heart is a linear tube comprising of cardiomyocytes (CMs) surrounded by nonmyocyte pericardial cells (PCs). Our recently published study showed that under normal, physiological conditions, levels of ROS are elevated in the PCs compared to the CMs. ROS in PCs activate a downstream D-p38 MAPK pathway that acts on the CMs to control their development and function. These findings provide new opportunities for us to elucidate the molecular mechanisms by which ROS could mediate the functional interaction between PC and CM, which will contribute to the achieving of our central aim. Building on our published and new preliminary data, we will further delineate the components and function of the physiological ROS-D-p38 signaling pathway in the Drosophila PCs. Our central hypothesis is that a signaling pathway comprised of ROS-D-p38 (PC) → Septate junction (SJ) proteins (PC) → TRPA channels (CM) → Ca2+ influx/signal transduction (CM) mediates the ROS-based paracrine interactions between PC and CM in the Drosophila heart. This hypothesis will be tested by three specific aims: (1) Determine the intracellular source(s) of ROS in pericardial cells, (2) Define the roles of SJ proteins as pericardial cell-specific targets of ROS-D-p38 signaling, and (3) Define the roles of TRPA ion channel proteins as cardiomyocyte-specific targets of ROS-D-p38 signaling. These aims will be addressed by a combination of genetic, bio-imaging and RNA-sequencing experiments. This project is expected to reveal novel and important insights into the poorly understood areas of ROS-based paracrine signaling and functional interactions between cardiac myocytes and nonmyocytes. This knowledge may facilitate the development of new and improved therapies for human heart disease and failure.

描述（由申请人提供）：摘要本研究的中心目的是定义活性氧（ROS）介导心肌细胞和非肌细胞之间相互作用的新型信号传导机制，这对于心脏的正常发育和功能至关重要。果蝇作为模型系统心肌细胞和非心肌细胞之间的细胞间通讯的扰动是心律失常、心源性猝死和心力衰竭的主要根源。因此，对于开发针对人类心脏病的新的和改进的疗法来说，果蝇心脏是阐明心肌细胞-非肌细胞功能相互作用的精确分子基础的模型系统。我们最近发表的研究表明，在正常生理条件下，与 PC 中的 CM 相比，PC 中的 ROS 水平升高。 D-p38 MAPK 通路作用于 CM 来控制其发育和功能，这些发现为我们阐明 ROS 介导 PC 和 CM 之间功能相互作用的分子机制提供了新的机会，这将有助于实现我们的目标。基于我们已发表的和新的初步数据，我们将进一步描述果蝇 PC 中生理 ROS-D-p38 信号通路的组成和功能。 ROS-D-p38 (PC) → 隔膜连接 (SJ) 蛋白 (PC) → TRPA 通道 (CM) → Ca2+ 流入/信号转导 (CM) 介导果蝇心脏中 PC 和 CM 之间基于 ROS 的旁分泌相互作用。假设将通过三个具体目标进行检验：（1）确定心包细胞中 ROS 的细胞内来源，（2）定义 SJ 蛋白在心包细胞中的作用ROS-D-p38 信号传导的细胞特异性靶标，以及 (3) 定义 TRPA 离子通道蛋白作为 ROS-D-p38 信号传导的心肌细胞特异性靶标的作用。该项目有望揭示基于 ROS 的旁分泌信号传导以及心肌细胞和非心肌细胞之间的功能相互作用的新的和重要的见解，这些知识可能有助于开发新的和改进的疗法。用于人类心脏病和衰竭。