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NO-mediated regulation of the pacemaker function and motility in the murine jejunum and colon

NO介导的小鼠空肠和结肠起搏器功能和运动的调节

基本信息

批准号：
299630640
负责人：
Professor Dr. Andreas Friebe
金额：
--
依托单位：
Physiologisches Institut
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/299630640?language=en
关键词：
NO mediated regulation pacemaker function

项目摘要

NO-sensitive guanylyl cyclase is involved in many physiological regulatory processes such as regulation of blood pressure, synaptic plasticity or gastrointestinal motility. The enzyme is activated by nitric oxide (NO) and catalyzes the formation of the second messenger cGMP. We have generated mice in which NO-GC is deleted globally. These mice suffer from gastrointestinal dysmotility, elevated blood pressure and premature death. However, the cell/tissue types responsible for the individual phenotypes are not yet clear.The reduced GI motility in global GCKO mice is based on the lack of the nitrergic (NO-mediated) relaxation. The exact mechanism of nitrergic relaxation is still not elucidated thoroughly. The identity of the cell types involved in mediating the effect of NO is still unclear as NO-GC is expressed in smooth muscle cells (SMC) as well as interstitial cells of Cajal (ICC), fibroblast-like cells (FLC) and even in certain neurons. Among ICCs, two different subtypes are of special interest with distinct functions: Myenteric ICC (ICC-MY) generate the pacemaker potential whereas intramuscular ICC (ICC-IM) are held responsible of enteric neurotransmission. The effect of neuronally released NO on these two types of ICC is being intensely discussed.In this project, we want to investigate how NO/cGMP regulate rhythmicity of the pacemaker system and spontaneous contractions in different colon and jejunum sections. We will use KO mice lacking NO-GC globally or specifically in SMC, ICC or both. Different parts of jejunum and colon will be taken from these animals for organ bath studies (spontaneous contractions) and microelectrode studies (slow waves). The expression of NO-GC and other members of the NO/cGMP signaling cascade will be investigated using immunohistochemistry. In addition, the ex vivo motility with isolated jejunum and colon from these KO animals will be measured. In all subprojects, we will investigate whether activation of the NO/cGMP system by the novel NO-GC activators/stimulators Bay 41-2272 or Bay 58-26678 (Cinaciguat) have a therapeutic potential with regards to gut motility. Data from murine tissues will finally be correlated to data obtained from human tissues. In summary, our NO-GC KO mice will help to elucidate how slow waves spontaneous contractions are interconnected and regulated by the nitrergic system.

一氧化氮敏感的胍基环化酶参与许多生理调节过程，如调节血压、突触可塑性或胃肠运动。该酶被一氧化氮（NO）激活并催化第二信使cGMP的形成。我们产生了全局删除NO-GC的小鼠。这些小鼠患有胃肠运动障碍、血压升高和过早死亡。然而，导致个体表型的细胞/组织类型尚不清楚。GCKO小鼠的GI运动性降低是基于缺乏氮能（no介导的）松弛。氮能松弛的确切机制仍未完全阐明。NO- gc在平滑肌细胞（SMC）、Cajal间质细胞（ICC）、成纤维细胞样细胞（FLC）中表达，甚至在某些神经元中表达，参与介导NO作用的细胞类型尚不清楚。在ICC中，有两种不同的亚型具有不同的功能：Myenteric ICC （ICC- my）产生起搏器电位，而肌内ICC （ICC- im）负责肠内神经传递。神经元释放的NO对这两种ICC的影响正在被广泛讨论。在这个项目中，我们想要研究NO/cGMP如何调节起搏器系统的节律性和结肠和空肠不同部位的自发收缩。我们将在SMC、ICC或两者中使用缺乏NO-GC的KO小鼠。将从这些动物身上取空肠和结肠的不同部位进行器官浴研究（自发收缩）和微电极研究（慢波）。免疫组织化学将研究NO- gc和其他NO/cGMP信号级联成员的表达。此外，还将测量这些KO动物离体空肠和结肠的离体运动性。在所有子项目中，我们将研究新型NO- gc激活剂/刺激剂Bay 41-2272或Bay 58-26678 （Cinaciguat）对NO/cGMP系统的激活是否在肠道运动方面具有治疗潜力。来自小鼠组织的数据最终将与来自人体组织的数据相关联。总之，我们的NO-GC KO小鼠将有助于阐明慢波自发收缩是如何相互关联并由氮系统调节的。