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.

无敏感的鸟叶基环酶参与许多生理调节过程，例如血压，突触可塑性或胃肠道运动。该酶通过一氧化氮（NO）激活，并催化第二信使CGMP的形成。我们已经生成了无需GC在全球删除的小鼠。这些小鼠患有胃肠道功能障碍，血压升高和过早死亡。然而，尚不清楚负责各个表型的细胞/组织类型。全球GCKO小鼠的GI运动降低是基于缺乏硝化（无介导的）松弛的基础。硝化弛豫的确切机制仍未彻底阐明。介导NO效应的细胞类型的身份尚不清楚，因为NO-GC在平滑肌细胞（SMC）以及CAJAL（ICC）（ICC），成纤维细胞样细胞（FLC）甚至某些神经元中表达。在ICC中，两种不同的亚型具有特殊功能，具有不同的功能：Myenteric ICC（ICC-MY）产生了起搏器电位，而肌内ICC（ICC-IM）则负责anteric神经传递。正在深入讨论NO对这两种类型的ICC的影响。在这个项目中，我们想调查/CGMP如何调节起搏器系统的节奏性以及不同柱廊和jejunum部分中的自发收缩。我们将在全球或SMC，ICC或两者兼而有之的NO-GC小鼠。空肠和结肠的不同部位将从这些动物中进行器官浴研究（自发收缩）和微电极研究（慢波）。 NO-GC和NO/CGMP信号级联的其他成员的表达将使用免疫组织化学研究。另外，将测量具有分离的空肠和结肠的离体运动。在所有次要投影中，我们将研究新型的NO-GC激活剂/刺激器BAY 41-2272或BAY 58-26678（CINACIGUAT）对NO/CGMP系统的激活是否具有有关肠运动性的治疗潜力。来自鼠组织的数据最终将与从人体组织获得的数据相关。总而言之，我们的NO-GC KO小鼠将有助于阐明慢速自发收缩如何通过氮气系统互连和调节。