Pnmt+心肌细胞对心脏交感神经细胞的反馈调控及机理研究

It is known that the sympathetic nerve regulates the function of the heart in one way through the secreting transmitter. However, so far little is known about their mechanism of communication between the myocytes and the sympathetic cells. We revealed a novel cardiomyocyte subpopulation, named as Pnmt+ cardiomyocytes, which has potential endocrine function. Their anatomical distribution characteristics are similar to that of sympathetic nerve innervation, suggesting that there is mutual communication between them. Based on these findings, we hypothesize that the functional interactions/communications between Pnmt+ cardiomyocytes and sympathetic nerve cells within the heart are crucial for maintaining cardiac-neuronal crosstalk and homeostatic regulation. To test this hypothesis, we propose three series of studies: firstly, we will explore the structural and functional interactions of Pnmt+ cardiomyocytes and sympathetic stellate neurons under physiological and pathological conditions. The studies will be carried out by using in vivo and in vitro models prepared from genetically modified mice. An integrated approach combining with electrophysiology, confocal, optical mapping, cellular and molecular biology and computation from whole organ to cellular and molecular levels will be conducted in the studies. The results obtained from the proposed studies will lead to an in-depth understanding of biological function of Pnmt+ cardiomyocytes and their role in cardiac-neuronal communication and homeostatic regulation.

已知交感神经通过分泌递质单向调控心脏功能,但有关心肌细胞与交感神经细胞间的交流机制研究甚少。我们发现了一类具有潜在内分泌功能的心肌细胞亚群-Pnmt+心肌细胞，其解剖分布特征与交感神经心脏支配相似,提示两者间存在相互交流。我们提出：Pnmt+心肌细胞与交感神经心脏支配末梢形成紧密的结构和功能耦联，通过反馈调控交感神经元来维持心脏-交感神经间的稳态。本课题采用光遗传Pnmt+细胞特异标记和Pnmt敲除等小鼠模型,结合电生理、激光共聚焦、计算模拟、光标测和分子生物学等手段;从细胞到器官多层次研究:确定Pnmt+心肌细胞肾上腺能信号及相关基因谱特征;确定它们与交感神经心脏支配末梢结构和功能的耦联关系;采用细胞条件培养模型明确Pnmt+心肌细胞与交感神经元间的交互作用及信号传递机制。本课题将阐明Pnmt+心肌细胞对心交感神经细胞的反馈调控和紧密物理连接模式,揭示心脏-神经细胞间交流和稳态调控机制。